Over the last quarter century, more than 532 genes have been put forward as regulatory targets of retinoic acid. In some cases this control is direct, driven by a liganded heterodimer of retinoid receptors bound to a DNA response element; in others, it is indirect, reflecting the actions of intermediate transcription factors, non-classical associations of receptors with other proteins, or even more distant mechanisms. Given the broad range of scientific questions continually under investigation, researchers do not always have occasion to classify target genes along these lines. However, our understanding of the genetic role of retinoids will be enhanced if such a distinction can be made for each regulated gene. We have therefore evaluated published data from 1,191 papers covering 532 genes and have classified these genes into four categories according to the degree to which an hypothesis of direct versus indirect control is supported overall.
We found 27 genes that are unquestionably direct targets of the classical pathway in permissive cellular contexts (Category 3 genes), plus 105 genes that appear to be candidates, pending the results of specific additional experiments (Category 2). Data on another 267 targets are not evocative of direct or indirect regulation either way, although control by retinoic acid through some mechanism is clear (Category 1). Most of the remaining 133 targets seem to be regulated indirectly, usually through a transcriptional intermediary, in the contexts studied so far (Category 0).
Background
Beginning in at least the late 1960s, there was tremendous interest in whether the differentiating and tumor suppressing activities of retinoids reflected a genetic mechanism, on analogy to the steroid hormones, or an epigenetic one. It had been known for some time that retinoids could influence mRNA levels in certain cells, but also that they could increase activity on membrane-bound ribosomes. Any number of different mechanisms were possible, and quite a few were proposed. In a particularly prescient statement of 1976, Sani and Hill (
1
) wrote, “The action of retinoic acid in reversing preneoplastic and neoplastic lesions may be due to a hormone-like effect involving induction and/or suppression of gene activity.” However, no conclusive experimental evidence had yet been adduced. As far as we know, it was Blalock and Gifford (2
) who first provided such evidence when they showed, in 1977, that interferon synthesis can be suppressed at a transcriptional level by a protein induced by all-trans retinoic acid (RA). To make their case they used transcription blockers, protein synthesis inhibitors, and a kinetic argument.It is now known that RA can influence gene expression and protein production in many ways, but in terms of molecular mechanisms, a single, predominant, classical pathway has emerged: all-trans retinoic acid plus a dimer composed of a retinoic acid receptor and a retinoid X receptor (an RAR.RXR dimer) and a more or less regular DNA response element. In this paper, genes that respond through this pathway are called “direct” targets of the classical RA pathway; those that respond to RA through other molecular mechanisms, but do respond, are called “indirect” targets. Since Blalock and Gifford's paper nearly a quarter century ago, more than 532 genes have been put forward as regulatory targets of RA; and while the distinction between direct and indirect regulation is now well entrenched, it is not necessarily germane to every study. Nevertheless, a great deal of suggestive data has been generated and it can be used to construct a tentative classification of RA's targets along these lines.
Constructing a classification table
There is a simple but powerful motivation for constructing such a classification: progress in understanding RA's role at a genomic or proteomic level will require determining which regulatory events are handled through which cellular circuits. This paper is an attempt to begin that process in a systematic way. In what follows, we have evaluated the experimental evidence presented in more than 1,191 published articles and have prepared a preliminary categorization of RA's targets according to the degree to which current research supports an hypothesis of direct versus indirect control. More specifically, we have constructed a table (see Gene Table at the end of this article) that briefly summarizes the experimental evidence available for each target gene and “rates” the degree to which the combined evidence supports or opposes the notion of direct regulation in at least one cellular context. Where the evidence is very strong, constituting proof or something close to it, we call the gene a Category 3 gene. Where the combined evidence suggests or demonstrates indirect regulation (in the contexts studied, and no other investigations show or suggest direct regulation elsewhere), we have called the gene a Category 0 gene. Categories 1 and 2 are positioned between these two, with the evidence for direct regulation somewhat stronger for Category 2 genes. All four categories are more rigorously characterized below.
It should be stressed that the numeric designations used for the categories are nothing more than tags. With a very few exceptions (which always clearly marked), the Category 0 genes are regulatory targets of RA every bit as much as Category 3 genes. They are simply regulated in different ways. Category 1 and Category 2 genes are also targets, although current research does not allow us to conclude quite so much about the mechanisms employed in these cases. Emphatically, the classification does not mean to impugn the work reported in the any of papers considered. The distinction between direct and indirect regulation is not necessarily relevant to many valid research goals, and a great deal of valuable work has been done in clinical, developmental, and basic science without addressing these questions even obliquely.
Of necessity, the Gene Table is long and complex. However, the genome projects, various proteomic studies, and the preliminary gene ontologies produced over the last few years have made it clear that work on some very interesting biological questions will require dealing with vast amounts of data. Gene expression regulation by RA encompasses a number of such questions and a compilation like the Gene Table would seem to be an economical way to approach some of them.
The classical RA pathway
Four basic concepts are central to any description of the classical RA pathway: ligand involvement, receptor dimerization, DNA binding, and the resulting transcriptional modulation of the gene (occasionally, one of the genes) whose regulatory element has been bound. It sometimes happens that the gene under investigation is not the gene whose regulatory unit has been bound, but that RA has regulated an intermediary which in turn regulates the gene of interest. In these cases, the intermediary factor (usually another transcription factor) may be a direct target, while the gene under study is an indirect target. Other types of indirect regulation include RA's ability to influence mRNA stability, to activate nuclear receptor dimers other than an RAR.RXR, and so forth.
It might seem arbitrary, uninformative, or unnecessarily stringent to restrict “direct” regulation to the classical RA pathway and to consign all other regulatory modalities to the catch-all category, “indirect” regulation. However, each alternative regulatory pathway represents a distinct type of genetic event. Perhaps each deserves its own Gene Table. We chose the classical RA pathway as a branch point in the present work, i) because of its preeminent historical position, ii) because the distinction between direct and indirect regulation through this pathway is well established and frequently studied, and iii) because many suggestive and highly relevant studies are available, even though questions of molecular mechanism are not necessarily raised in them.
The Gene Table is intended to cover every gene now known to be regulated by retinoic acid. The last attempt at delineating a complete set of such genes was published by Chytil and Raiz-ul-Haq in 1990 (
3
). They listed more than 125 proteins that we now take to be monogenic, plus a number of other proteins of less clear provenance. Gudas et al. took a slightly different starting point 4 years later, and wrote detailed descriptions of most RA targets known at the time. They categorized them primarily along functional or homology lines (4
).Literature reviews
Retinoid science is an immense field. Two recent reviews, both of which are comprehensive within their scopes but neither of which attempts a complete list of RA-regulated genes, are by Nagpal and Chandraratna (
5
) and a cross-lab group led by De Luca (6
). Two more specialized reviews, on receptor-specific ligands (7
) and on discoveries made through receptor knockouts (8
), expand on topics that turn up frequently in the Gene Table, but are treated only generically. Beyond these, virtually every area of regulatory, clinical, and developmental application has its own reviews. To mention just a few, see () for retinoid metabolism, (10
) for retinoids and cancer, (11
) or (12
) for two topics in developmental work, and (13
) for dermatological issues. An updated collection of methods papers has recently been published. It contains valuable information on traditional as well as innovative experimental techniques involving the retinoids, their receptors, and associated molecules. See (14
) and the papers following it. A detailed characterization of what is currently known about the molecular and even atomic mechanisms that permit direct RA-activated transcriptional regulation is presented in (15
). Although these events are beyond the scope of the present paper, they underpin many of the routes of gene regulation covered here.The retinoid receptors are members of a much larger group of transcription factors, the so-called nuclear receptors. An encyclopedic overview of this large and important class of proteins is Gronemeyer and Laudet's 1995 monograph (
16
). It remains invaluable even though its publication preceded some of the more recent work on co-regulators, intermediary factors, and the chromatin connection. For an update in those areas, see Rosenfeld and Glass (17
). Chawla et al. (18
) recently reviewed the connection between the nuclear receptors and lipid physiology, and both RARs and RXRs play roles in this. Finally, two collections of particularly noteworthy reviews appeared in the mid-1990s: one covering various aspects of the nuclear receptors and the other, various aspects of the retinoids. See (19
) and (), respectively, and the articles that accompany them.METHODS
Selecting genes for inclusion in this analysis
The Gene Table does not cover every gene ever investigated in conjunction with retinoic acid, although we hope it includes every known target. Because RA has the power to initiate fundamental phenotypic changes in many cells, it is sometimes used only as an agent to set up an experiment: differentiated versus non-differentiated cells, for example. Genes investigated only in such settings were excluded. Overall, our basic filter for including or excluding genes was whether or not an explicit claim of regulation by retinoic acid had been advanced. We did not require that the regulation be attributed to the classical RA pathway. In some cases, direct regulation was investigated or implied; in others it was indirect regulation; and in some, the mode of regulation was not addressed, either explicitly or implicitly.
Although we made every effort to identify and follow up on “novel” genes identified in differential display-type experiments, we have not included any genes so totally uncharacterized that they have not yet even been named. See (
21
) for some examples. Nor have we included fragments so far identified only as ESTs. See (22
) and (23
) for examples of these.An analysis of this sort would ideally be limited to work done in “normal” cells or individuals; the activities of RA and its receptors in aberrant cell types would then be handled separately as exceptions. We have tried to do this up to a point. Work on cells that have suffered catastrophic DNA events that are likely to have affected RA's activity, certain viral integrations, extraordinary recombinations, engineering experiments, and the like, have been excluded except to make occasional special points. In particular, work on acute promyelocytic leukemia (APL) cells, which generally express oncogenic RARα fusions, have been largely excluded on this ground. Nevertheless, a great deal of research has been done on RA's activities in APL cells and we refer the reader to (
24
) for a review. Of course, many common cell lines contain genomic anomalies that are not likely to have affected RA's activity overall: HepG2 and Caco-2 lines, for example. For the purposes of this work, such cell lines are considered normal.As a rule, we did not consider experiments in which RA was used in conjunction with another treatment, although we tried to take note of any controls using RA alone. The exception to this is where some form of external “activation” seems to be required for any expression of the target gene, for example, the interleukins. It should be stressed that by excluding combo-treatments we automatically ruled out many studies using RA plus cAMP (or RA plus cAMP and theophylline) rather than RA alone. We did, however, consider these experiments if they confirmed points suggested elsewhere by RA alone. This is an admitted limitation of the present work, but the complexity of regulatory interactions in these cases is still overwhelming.
Constructing a database of papers and genes
Using various free text and MeSH (Medical Subject Headings) strategies at the United States National Library of Medicine's PubMed gateway, we created a database of more than 4,000 papers relevant to the regulation of gene expression by retinoic acid. We identified the gene or genes considered in each paper, and, based on abstracts, selected what appeared to be the most relevant studies for each gene. Using this set of abstracts and the associated MEDLINE coding, we determined which species had been investigated, located the gene's official name at LocusLink (
25
), and performed supplementary searches based on official nomenclature, curated aliases, and any novel names or aliases applied to orthologs. This process was iterated as necessary, and eventually led to a list of relevant papers for each gene. These entries were then re-evaluated at the abstract level and the most promising papers (for our purposes) were gathered and consulted for data, discussions, and further citations. New candidate genes went through the same process as they turned up. By the end of the project, nearly 8,000 papers (not including reviews) had been considered to one degree or another.For each gene, we then studied the scientific evidence presented in the selected papers and evaluated the degree to which a direct regulatory pathway had been demonstrated, suggested, or brought into question. This information was distilled into several short standardized phrases and incorporated into the Gene Table, along with species information, any alternative names and symbols used in the selected studies, and references to the most essential papers.
Concordance of working and official gene names
Most genes have several names. By “official nomenclature” we mean names and symbols approved by (or pending before) the Human Genome Organization Nomenclature Committee, the Mouse Genome Informatics Nomenclature Committee, the International Rat Genetic Nomenclature Committee, or the Zebrafish Nomenclature Committee. We have followed official nomenclature whenever possible. This can be confusing when the official name of a gene is either uninformative, uncommon, or simply designed for a purpose that is not one's own. For example, most readers probably would not recognize Nr2f1 as the name of the gene that encodes COUP-1. However, while understandable from a historical perspective, the proliferation of trivial names (for both genes and proteins) has been scientifically unhelpful and using official names solves the problem. The lists of alternatives and aliases kept by the nomenclature committees and at LocusLink should quickly resolve any questions.
It is not always easy to determine which gene has been studied in a given paper, or which papers deal with the same gene; and this is not limited to older papers. It can be particularly problematic when several species, or several apparently unrelated scientific questions, have been studied in different papers. In a number of cases, we had to align published primer sequences with groups of homologs, follow LinkOuts to cited sequences at the National Center for Biotechnology Information's Entrez system, or even BLAST nucleotides strings taken from journal figures.
As a rule, the Gene Table uses the gene symbol from the species discussed in the earliest paper cited; when no approved, pending, or interim name was available for the gene in that species, we generally chose the mouse version. The nomenclature committees try to keep symbols and leading phrases invariant over vertebrate species (except for orthographic differences) so this is little more than a matter of choice. In order to save space, only symbols, not full names, are used in the first column of the table.
Trivial names from cited papers
The second column of the Gene Table, “Name in refs,” lists only the gene or protein designations used in the papers cited. It does not include other aliases, no matter how common they may be in the literature. Table 1 provides a concordance between these working names (or abbreviations) and the symbols used in the Gene Table, but only for cases where the two are very different. Throughout, we have suppressed the distinction between genes and the proteins they encode.
TABLE 1Concordance of trivial names and symbols
| Common Name | Gene Table |
|---|---|
| 14.5-D lectin | Lgals1 |
| 25-hydroxyvitamin D3-24-hydroxylase | CYP24 |
| 34 kDa lectin | Lgals3 |
| 92 kDa gelatinase | MMP9 |
| A4 | Clta |
| ACS | FACL2 |
| Activin A | INHBA |
| Acyl-coA synthase | FACL2 |
| ADD1 | Srebf1 |
| ADH3 | ADH1C |
| Aggrecanase | ADAMTS4 |
| α 1-microglobulin | Ambp |
| α-SM | Acta2 |
| Aminopeptidase-B | RNPEP |
| AML2 | RUNX3 |
| ANF | Nppa |
| ANP | Nppa |
| Antithrombin III | SERPINC1 |
| AP-2 | TFAP2A |
| AP-2.2 | Tcfap2c |
| Ap-B | RNPEP |
| Apolipoprotein(a) | LPA |
| ARP-1 | Nr2f 2 |
| Arrestin | SAG |
| ATX | ENPP2 |
| β 1-AR | Adrb1 |
| β-amyloid precursor protein | App |
| Bone sialoprotein (BSP) | IBSP |
| Bone sialoprotein I | Spp1 |
| Brn-3.2 | Pou4f 2 |
| c-abl | Abl1 |
| Calcineurin A | PPP3CA |
| Calcineurin B | PPP3CB |
| CBFA3 | RUNX3 |
| CD10 | MME |
| CD11a | ITGAL |
| CD11b | ITGAM |
| CD15 | Fut4 |
| CD157 | BST1 |
| CD18 | ITGB2 |
| CD23 | FCER2 |
| CD31 | PECAM1 |
| CD43 | SPN |
| CD50 | ICAM3 |
| CD51 | Itgav |
| CD71 | TFRC |
| CD82 | KAI1 |
| CD95 | PTPN13 |
| CD95 | TNFRSF6 |
| CD95 ligand | Tnfsf6 |
| c-fms | CSF1R |
| Cg B | Chgb |
| CGRP | Cal1 |
| Cholesterol sulfotransferase | SULT2B1 |
| CIP1 | Cdkn1a |
| CL-20 | EMP1 |
| clusterin | Trpm2 |
| c-myb | MYB |
| c-myc | MYC |
| Collagenase | MMP1 |
| Connexin31 | Gjb3 |
| Connexin43 | Gja1 |
| Contact | Gdf 5 |
| Cornifin | SPRR1B |
| COUP-TF II | Nr2f 2 |
| COUP-TF1 | Nr2f1 |
| COX-1 | Ptgs1 |
| COX-2 | PTGS2 |
| CRBPI | Rbp1 |
| CRBPII | Rbp2 |
| CT | Cal1 |
| Common Name | Gene Table |
| Cu/Zn superoxide dismutase | Sod1 |
| Cx43 | Gja1 |
| Cyclin D3 | CCND3 |
| Cyclin E | Ccne1 |
| Cyclooxygenase-1 | Ptgs1 |
| D3 | Dio3 |
| D9 | Stra13 |
| DEAD box protein | DDX1 |
| DEAD box protein p72 | DDX17 |
| D-III | Dio3 |
| Dopamine D2 receptor | Drd2 |
| DOR | OPRD1 |
| Drg1 | NDRG1 |
| Dystroglycan α, β | DAG1 |
| E3 | Laptm5 |
| EAT | MCL1 |
| E-cadherin | CDH1 |
| E-MAP-115 | Mtap7 |
| EndoA | KRT8 |
| EndoB | KRT18 |
| Endolyn | Cd164 |
| eNOS | NOS3 |
| Epithelin | Grn |
| ERA-1 | Hoxa1 |
| Erk2 | Mapk1 |
| ET-1 | EDN1 |
| F1 | Ngp |
| F3 | Cntn1 |
| FAK | PTK2 |
| Fas | TNFRSF6 |
| FasL | Tnfsf6 |
| FATP | SLC27A1 |
| FBPase isozyme | Fbp2 |
| FGF-BP | HBP17 |
| Focal adhesian kinase | PTK2 |
| Fra-1 | Fosl1 |
| Fru-1, 6-P2ase | Fbp1 |
| Galectin-7 | LGALS7 |
| GCNF | Nr6a1 |
| Gelatinase A | MMP2 |
| Gene 33 | MIG-6 |
| GLUT 2 | Slc2a2 |
| GLUT 3 | Slc2a3 |
| gp91-phox | CYBB |
| gp96 | TRA1 |
| GR | NR3C1 |
| GST 5.7 | Gsta4 |
| H218 | Gpcr13 |
| HAKR e | AKR1C3 |
| HB-EGF | DTR |
| HER4 | ERBB4 |
| HERG | KCNH2 |
| HGFL | MST1 |
| HIOMT | ASMT |
| hlx-1 | dbx1a |
| HNF-1 α | Tcf1 |
| HNF-1 β | Tcf2 |
| HNF-3 β | Foxa2 |
| HNF-3 α | Foxa1 |
| Hox-1.6 | Hoxa1 |
| HOX3D | HOXC5 |
| Hox-2.b | Hoxb4 |
| Hox-4.2 | Hoxd4 |
| hRDH-TBE | RDHL |
| HSP86 | Hsp86-1 |
| HSP90 | Hsp86-1 |
| HSPCA | Hsp86-1 |
| HSPG | SDC2 |
| Htf 9-a/RanBP1 | Ranbp1 |
| IAP | ALPI |
| ICE | CASP1 |
| Osteopontin | Spp1 |
| OT | OXT |
| p15 | CDKN2B |
| p190 GAP-associated protein | Arhgap5 |
| p21 | Cdkn1a |
| p34(CDC2) | CDC2 |
| P450RAI | Cyp26 |
| p47-phox | NCF1 |
| p53 | Trp53 |
| p67-phox | NCF2 |
| p68 kinase | PRKR |
| p75NTR | Ngfr |
| PACAP | ADCYAP1 |
| PACAP1 (Type I) receptor | ADCYAP1R1 |
| PACAP2 (Type II) receptor | VIPR1 |
| PAFR | PTAFR |
| PAI-1 | SERPINE1 |
| PAI-2 | SERPINB2 |
| P-cadherin | CDH3 |
| PCD5 | Pcp2 |
| PCDHX | PCDH11 |
| PCDHY | PCDH22 |
| PEPCK | Pck1 |
| PGHS1 | Ptgs1 |
| PGHS2 | PTGS2 |
| pgp1 | ABCB1 |
| PK | Pk3 |
| PKC | Pkca |
| PKC β 1 | PRKCB1 |
| Placental lactogen | CSH1 |
| Plasminogen activator inhibitor 1 | SERPINE1 |
| Plasminogen activator inhibitor 2 | SERPINB2 |
| pRbAp46 | Rbbp7 |
| proinsulin | INS |
| promyelocytic defensin-1 | DEFA1 |
| ProT α | PTMA |
| Psoriasin | S100A7 |
| PTHrP | Pthlh |
| RA28 | FXYD3 |
| Rae-28 | Edr1 |
| Rae-30 | Fbp2 |
| Rb | RB1 |
| RBP | RBP4 |
| RC3 | NRGN |
| RDH | Rsdr1 |
| Retinal fascin | FSCN2 |
| Rex-1 | Zfp42 |
| Rh1 | Rho |
| RIG1 | RARRES3 |
| RIHB | Mdk |
| RIP140 | NRIP1 |
| RIS-1 | S100A7 |
| RMUC176 | Muc3 |
| Rod-specific opsin | Rho |
| RTP | NDRG1 |
| RTR | Nr6a1 |
| S14 | Thrsp |
| Sar1a | Sara |
| SCCE | KLK7 |
| SCF | Kitl |
| Sgp-2 | Trpm2 |
| SLAP | SLA |
| SPA | Sftpa1 |
| SP-B | SFTPB |
| SP-C | SFTPC |
| Spr1 | SPRR1B |
| SSAT | Sat |
| SSEA-1 | Fut4 |
| SSeCS | Akap12 |
| ST3 | MMP11 |
| Stem cell factor | Kitl |
| Ikaros | Znfn1a1 |
| IL-1b stimulating gene | BIRC3 |
| Importin α | Kpna2 |
| INK4B | CDKN2B |
| iNOS | Nos2 |
| J6 serpin | Serpinh1 |
| K2e | KRT2A |
| K6 | KRT6A |
| k-casein | Csnk |
| K-FGF | FGF4 |
| KOR | Oprk1 |
| Krox-24 | Egr1 |
| L-14 | Lgals1 |
| L-34 | Lgals3 |
| Lamins A/C | Lmna |
| Lefty | Ebaf |
| Lewis x | Fut4 |
| LFA-3 | CD58 |
| Liver/bone/kidney AP | Akp2 |
| l-myc | MYCL1 |
| LNGFR | Ngfr |
| LOX-1 | Olr1 |
| LPL | Lpl |
| l-selectin | SELL |
| MAC-1 | ITGAM |
| Major histocompatibility class I (H2K, -D, -L, -Q, etc.) | H2 |
| MASH1 | Ascl1 |
| Mash-2 | Ascl2 |
| MCAD | ACADM |
| MCP-1 | SCYA2 |
| M-CSF | CSF1 |
| mda-6 | Cdkn1a |
| MDR1 | ABCB1 |
| mdr3 | ABCB1 |
| Meis2 | Mrg1 |
| MK | Mdk |
| MLN/CAB1 | MLN64 |
| MnSOD | SOD2 |
| MOR | OPRM1 |
| Mox1 | Meox1 |
| mph1 | Edr1 |
| mrp2 | ABCC2 |
| MRP-8 | S100A8 |
| Msx-1 | Msx2 |
| mWnt-8 | Wnt8d |
| MZF-1 | ZNF42 |
| Na, K-ATPase | Atp1a3 |
| Na+/H+ antiporter | SLC9A1 |
| N-cadherin | CDH2 |
| Ndr1 | NDRG1 |
| NEP | MME |
| NGFI-B | NR4A1 |
| NHE-2 | Slc9a2 |
| NIS | SLC5A5 |
| NKX3.2 | Bapx1 |
| nm23-H1 | NME1 |
| NMDAR1 | GRIN1 |
| NN8-4AG | Rrg1 |
| nNOS | NOS1 |
| NOR-1 | NR4A3 |
| NSP-A | RTN1 |
| NSP-C | RTN3 |
| ntcp | SLC10A1 |
| Nur77 | NR4A1 |
| Nurr1 | NR4A2 |
| ob | Lep |
| Oct3 | Pou5f1 |
| Oct3/4 | Pou5f1 |
| OP | Spp1 |
| Osteocalcin | BGLAP |
| Osteonectin | Sparc |
| Stra1 | Efnb1 |
| Stra10 | Mrg1 |
| Stra11 | Wnt8d |
| Stra3 | Ebaf |
| Stra7 | Gbx2 |
| Stromelysin | MMP3 |
| Stromelysin-3 | MMP11 |
| Survivin | BIRC5 |
| TBRII | Tgfbr1 |
| TF | F3 |
| TF CA150 | TAF2S |
| TfR | TFRC |
| TGase K | Tgm1 |
| TIG1 | RARRES1 |
| TIG2 | RARRES2 |
| TIG3 | RARRES3 |
| TIS10 | PTGS2 |
| Tissue factor | F3 |
| TM | THBD |
| TNAP | Akp2 |
| TopoII | TOP2A |
| t-PA | PLAT |
| TR2-11 | Nr2c1 |
| TR4 | NR2C2 |
| TrkA | Ntrk1 |
| Trkb | Ntrk2 |
| TrkC | NTRK3 |
| TRP-2 | DCT |
| Ulip | DPYSL3 |
| u-PA | PLAU |
| VAChT | Slc18a3 |
| Vesicular acetylcholine transporter | Slc18a3 |
| Vitronectin receptor | Itgav |
| WAF1 | Cdkn1a |
| Xlim-1 | Lhx1 |
| Y1R | NPY1R |
| zif 268 | Egr1 |
Concordance of common names and the official symbols used in the Gene Table for cases where there are significant differences between them.
Tabled
1
| Symbol | Name in Refs | Spp | Dir | Summary | Ref PMIDs | Cat |
|---|---|---|---|---|---|---|
| ADH1C | ADH3 | Hs | Up | Induction; functional binding site; negative TRE nearby. | 0001996113; 0001321136; 0008388158 | 3 |
| CD38 | CD38 | Hs, Mm | Up | Induction; differentiation controls; specific ligands; functional binding sites; evidence from transgenics. | 7690555; 0008394323; 0007511050; 0009160665; 0009624127; 10969805 | 3 |
| Cdx1 | Cdx1 | Mm, Hsa | Up | Induction; conserved functional binding site. | 7649373; 10938132 | 3 |
| CEBPE | C/EBP epsilon | Hs | Up | Rapid induction during differentiation; functional binding site; specific ligands. | 9376579; 9177240; 0010330422 | 3 |
| CRABP2 | CRABP-II | Hs, Mm | Up | Induction; conserved functional binding sites. | 0001654334; 1309505; 0001313808; 0001327537; 0001334086; 0008071361; 0009856825 | 3 |
| Cryab | αB-crystallin/small HSP | Mm | Up | Induction; functional binding site. | 0009651402 | 3 |
| Drd2 | dopamine D2 receptor | Hs, Mm, Rn | Up | Induction; functional binding site; evidence from transgenics. | 7990648; 0009405615; 0009721718; 9452386 | 3 |
| Egr1 | Egr-1, zif268, Krox-24 | Mm, Rn | Up | Induction; functional binding site (characterized as a single half-site). | 1936556; 1793734; 1708092; 0007877619; 8176254 | 3 |
| ETS1 | Ets1, ets-1 | Hs, Mm | Up | Rapid induction during differentiation; functional binding motifs (single hexamer and DR5). | 3060792; 7689222; 0010773887; 11327309 | 3 |
| Foxa1 | HNF-3α | Mm | Up | Rapid induction during differentiation; no protein synthesis required; functional binding site. | 8029022; 7649373; 9260895; 0010388516 | 3 |
| H1F0 | H1° histone, H1 degree | Mm, Hs | Up | Early induction during differentiation; functional binding site (DR8); other NRs. | 2846273; 1988682; 0008078070; 0007576177; 0008559662 | 3 |
| Hoxa1 | ERA-1, Hox-1.6, Hoxa-1 | Mm, Dr | Up | Induction; conserved functional binding site; whole animal evidence (including transgenics). | 0003422432; 0002906112; 0001360810; 0007743939; 0008631251; 0008999919; 0009053316 | 3 |
| HOXA4 | hoxa-4 | Hs, Mm | Up | Induction; upstream functional binding site and downstream RA-responsive enhancer; whole animal evidence including transgenics; site conservation. | 0008759021; 0009570764; 9272954; 0010679930 | 3 |
| Hoxb1 | Hoxb-1 | Mm, Gg, Tr, Hs | vrsb | Induction; functional binding sites (5′ and several 3′); whole animal evidence including transgenics; site conservation. | 0007914354; 0007916164; 0007831296; 0007831297; 0008999919; 0009463349; 0009671595; 0009869297 | 3 |
| Hoxb4 | Hox-2.6, Hoxb-4 | Mm, Tr, Gg | Up | Induction; conserved functional binding site; evidence from transgenics. | 0007878040; 9272954; 0009697850 | 3 |
| Hoxd4 | Hox-4.2, Hoxd-4 | Mm, Hs | Up | Induction; functional binding sites (5′ and several 3′); whole animal evidence including transgenics; site conservation; some discussion that at least some effects may be indirect. | 2898782; 0008093325; 0007908827; 0008674428; 0009360992; 0009347914; 10940626 | 3 |
| HSD17B1 | 17HSD type 1c | Hs | Up | Induction; specific ligands; functional binding site. | 0008013376; 0008614400; 9048588 | 3 |
| IL2RA | IL-2R α | Hs | Up | Induction; an upstream region at least partly responsible has been identified; additional paracrine effect from RA induction of IL2 has been discussed. | 7678784; 0008157276; 9130512 | 3 |
| Pck1 | PEPCK | Rn, Hs, Mm | Up | Induction; functional binding sites; whole animal evidence; other NRs. | 2176887; 0001848696; 0001656224; 0007831301; 0008626419; 0009078282; 9202079 | 3 |
| Pit1d | Pit-1 | Mm, Rn, Ma, Hs | Up | Induction; conserved functional binding site (also acts as VDRE); Pit1 binding required for activity; clinical evidence. | 0008504933; 0007588287; 0009027335; 0010077004 | 3 |
| RARA | RAR-α2 | Hs, Mm, Tr | Up | Isoform 2 induction; conserved functional binding site. | 2825025; 2825036; 0001658797; 0010452951 | 3 |
| RARB | RARβ | Hs, Mm, Rn, Gg | Up | Induction (isoforms 2, 4); conserved functional binding site; isoforms 1, 3 appear not be RA regulated. | 2833708; 2836738; 0002542014; 0002153268; 0002177841; 0002164682; 0001663808; 0008384988; 0008011555; 7649373; 11073974 | 3 |
| RARG | RAR γ | Hs, Mm, Rn | Up | Isoform 2 induction; conserved functional binding site. | 0001320193; 0008394693; 0009142499 | 3 |
| Rbp1 | CRBPI | Mm, Rn | Up | Induction; conserved functional binding site. | 2546063; 0001648481; 0001339275 | 3 |
| SFTPB | SP-B | Hs, Rn, Mm | Up | Induction; region responsible for RA effect binds receptors; indirect effect likely as well; functional motifs; evidence from dominant negative. | 0008404646; 0008944731; 0009575874; 0009700083; 0010070102; 0010617585 | 3 |
| Tgm2 | TGase 2 | Mm, Hs, Rn | Up | Induction; controls for differentiation; specific ligands; unusual functional binding site of three hexamers: hex(n7)hex(n5)hex; requirement for both RA and 9-cis, at least in some systems. | 6149218; 2859286; 2900242; 2565341; 1705423; 9516142; 0008626785; 9516142 | 3 |
| Ucp1 | ucp, upc-1 | Rn, Mm | Up | Induction; conservede functional binding sites; specific ligands; whole animal studies; other NRs/factors. | 0007929091; 0007890689; 0008754778; 0008940169; 9659286; 10921912; 0010600643 | 3 |
| ABCC2 | mrp2 | Hs, Rnf | Up | Natural induction not shown (Rn promoter plus exogenous RARa.RXRa in Hs cells); dose not clear; binding site functional in hybrid system. | 0010722729 | 2 |
| ACADM | MCAD | Hs | Up | Reporter induction; functional binding site; other NRs; considerable discussion of physiological relevance. | 0001328196; 0008314750; 8754802; 0009271417 | 2 |
| Adrb1 | β 1-AR | Rn, Mm | Up | Induction during differentiation (although rapid in some systems); functional binding site (also DR5 TRE); appears indirect at least in some systems. | 9025717; 0009441829; 0009448745 | 2 |
| Akp2 | TNAP, liver/bone/kidney AP | Mm, Rn, Hs | Up | Induction; motif; an additional (and perhaps more important) indirect enhancement of steady state mRNA levels may occur during precursor mRNA processing. | 1849403; 1939166; 0008071372; 0008817450; 0010530919; 0010691970 | 2 |
| APOA1 | apo A-I | Hs, Mf, Rn | Upg | No good d/t data; several functional binding sites; possibly RXR.RXR; other NRs; specific ligands; at least one study found opposite in vivo and in vitro effects. | 0001646397; 8399088; 0007918317; 0007658149; 0008626539; 0008604295; 0009392425; 0010194513 | 2 |
| APOA2 | apo A-II | Hs, Rn | Up | No good d/t data; specific ligands; functional binding site; possibly RXR.RXR; RXR transfection may activate without addition of ligand; other NRs; no RA effect in some systems. | 0007918317; 0008668150 | 2 |
| APOC3 | apolipoprotein C-III | Hs | Up | No good d/t data; several functional binding sites; other NRs; specific ligands; possibly RXR.RXR. | 0009691099; 0009893992 | 2 |
| APOD | apoD | Hs | Up | Induction; independent of protein synthesis; specific ligands. | 7929425; 8943263 | 2 |
| ASMT | HIOMT | Hs | Up | Induction. | 8752109 | 2 |
| AT-RA 6h | AT-RA 6 | Hs | Up | Induction. | 0009415824 | 2 |
| BIRC3 | IL-1b stimulating gene | Hs | Up | Induction. | 11146166 | 2 |
| CDKN2B | p15, INK4B | Hs | Up | Induction with borderline d/t conditions; no significant change reported (but data not shown) in one short-term mRNA study. | 10479451; 10812241 | 2 |
| CETP | CETP | Hs | Up | No good d/t data; reporter induction (measured at 48 h); region responsible for RA effect identified and binding verified. | 0010329401 | 2 |
| Cfh | complement factor H | Mm | Up | Induction possible but not clearly showni; functional binding site. | 0001700780; 1828229 | 2 |
| CHAT | ChAT | Hs, Mm | Up | Induction, but d/t borderline; many studies have been in differentiating systems; potential motifs; specific ligands; other NRs; may be at least partly post-translational. | 2924123; 2924124; 8057782; 7919195; 0007673184; 0007790895; 7745608 | 2 |
| Crabp1 | CRABP I | Mm, Rn | vrs | No good d/t data; appears to be part of a complex autoregulatory system; binding motif; may require protein synthesis; several indirect mechanisms have been proposed, as well as direct regulation. | 2546063; 8382159; 0007528580; 7588278; 0008617785; 0008663043; 0009392513; 9142496; 9390004; 0010714763 | 2 |
| Crygf | γ F-crystallin | Mm | Up | No good d/t data; a functional binding site is also functional for the TR and ROR systems. | 0008436299; 0007877618; 0007650034 | 2 |
| CSH1 | placental lactogen | Hs, Rn | Up | No good d/t data; functional binding sites; other NRs. | 8174790; 0007867602; 0007589779; 0007867602 | 2 |
| Csnk | k-casein | Mm | Up | Induction. | 7649373 | 2 |
| CTSKj | cathepsin K/OC-2 | Oc | Up | Induction. | 0007639684 | 2 |
| CYP24 | 24(OH)ase, 25-hydroxyvitamin D3-24-hydroxylase | Rn, Hs, Mm | Up | No good d/t data; functional binding sites (which are also VDREs); specific ligands; that RAR.VDR or RXR.VDR may explain RA induction has not been conclusively ruled out. | 0007592579; 0009228086 | 2 |
| Cyp26k | P450RAI, CYP26AI | Dr, Mm, Hs | Up | Induction (but long-term exposure may lead to repression); specific ligands. | 0008939936; 0009228041; 0009250660; 0009740237; 0009442090; 0009716180; 0010583049; 11023996 | 2 |
| DTR | HB-EGF | Hs, Mm | Up | Induction; evidence from transgenics. | 9858142; 0010075925 | 2 |
| Ebaf | Lefty, Stra3 | Mm, Gg | Up | Induction; binding motif (Pal8); appears indirect, at least in some systems. | 7649373; 0009496783; 0010331971; 0010500184 | 2 |
| Edr1 | Rae-28, mph1 | Mm | Up | Early induction during differentiation. | 0008070621; 0010653359 | 2 |
| Efnb1 | Stra1 | Mm | Up | Induction. | 7649373 | 2 |
| EGFR | EGF receptor | Mm, Rn, Hs | vrs | Induction shown in some systems; d/t data for reduction (where it occurs) is not good; exogenous RAR plus nuclear proteins bind an identified upstream region; other NRs; there have been several proposals for indirect mechanisms. | 6245371; 2540431; 2783693; 0002169350; 1748717; 0001515368; 0007859922 | 2 |
| Epo | Epo | Rn, Mm, Hs | Up | No good d/t data; functional binding site; other NRs; evidence from receptor knockouts. | 8050571; 11050012; 11297512 | 2 |
| Fbp2 | Rae-30, FBPase isozyme | Mm | Up | Early induction during differentiation. | 0008070621; 8034042 | 2 |
| FOLR1 | folate receptor α | Hs, Mm | Up | Induction; no motif found. | 7707421; 10216260 | 2 |
| Gbx2l | Gbx-2, Stra7 | Mm, Xl | Up | Induction, but at least partly indirect (Hoxa-1). | 7649373; 8601031; 8652408; 10942599 | 2 |
| Gdf5 | Contact | Dr | Up | Induction (using dechorionated embryos soaked in RA-solution then extensively washed). | 0009256353 | 2 |
| Gh1 | GH | Rn, Hs | Up | Induction; functional binding site; specific ligands; other NRs; indirect in some systems but possibly not all; other factors, such as Pit1, may be required for effective induction. | 0002707148; 0008384845; 0007956917; 0008524311; 0008768885; 0009737723 | 2 |
| Glut4 | GLUT4 | Rn | Up | Some data hard to interpret; induction likely; other NRs. | 8119934; 7758830 | 2 |
| Gnrh1 | GnRH | Rn | Up | Induction; other NRs; (weak) functional binding site. | 0009526050; 11245923; 11245924 | 2 |
| GPX2 | Gpx2 | Hs | Up | Induction likely (but early data hard to read); motifs. | 0010498757 | 2 |
| GSTP1m | GSTP1-1, GSTP1*C | Hs | vrs | No good d/t data; repression appears indirect (AP-1 or tTG), however, induction may be direct; functional binding site. | 8546677; 0009407047; 0009679546; 0010536361 | 2 |
| H2 | major histocompatibility class I (H2K, -D, -L, and -Q, etc.) | Mm, Hs, vrsn | Up | No good d/t data; functional binding sites, one of them highly conserved. | 0003467324; 0001736309; 0008413217; 0008604312; 0008618036; 0009758167; 0009790391 | 2 |
| HSD17B2 | 17 β-HSD type 2 | Hs | Up | Induction; specific ligands. | 11397877 | 2 |
| Igf1 | IGF-I | Rn | vrs | Rapid induction in some differentiating systems (followed by late decrease); down-regulation in probably indirect. | 1572288; 0009258346 | 2 |
| Igf bp6 | IGFBP-6 | Rn, Hs | vrs | Associated with growth or differentiation regulation; induction; motif and somewhat conserved functional binding site (DR15); at least partly indirect in some systems (protein synthesis and mRNA stability for induction, Hoxa-1 for reduction). | 0007682065; 0008603611; 10942599; 11267670 | 2 |
| Il1a | IL-1 α | Mm, Hs | Up | Induction of pre-mRNA; may require additional special factors for processing. | 0008083217; 0007763262 | 2 |
| IL1B | IL-1 β | Hs | Up | Induction of pre-mRNA likely; RA may also have an effect secondary to induction by other transcription activators. | 0001646841; 0008489769; 0008360592; 0008083217; 0008702428; 0009783809 | 2 |
| IL2RB | IL-2R β | Hs | Up | Induction; upstream control region not found. | 7678784; 9268495 | 2 |
| IRF1 | IRF-1 | Hs | Up | Induction (independent of GAS motif). | 8704165; 9393879; 10319996 | 2 |
| Itgb3 | β 3 integrin | Gg | Up | No good d/t data; functional binding site overlaps a VDRE; other NRs. | 0008891892; 0008702813 | 2 |
| KRT5 | K5 | Hs | Dn | Suppression; an upstream cluster of hexamers that can bind RAR and suppress a CAT reporter has been found; AP-1 regulation; other NRs. | 1711202; 0007505782; 7505756; 7519609; 0009326392 | 2 |
| Lamb1-1 | laminin B1 | Mm, Hs | Up | Delayed induction in RA-differentiable cells; unusual putative RAR binding site that is somewhat conserved; induction requires protein synthesis; evidence from knockouts and lacZ transgenics; may be directly regulated but in an unusual way, perhaps. | 6310600; 0002981185; 0002842348; 0002556699; 0001975589; 0001850696; 11335108 | 2 |
| Lhx1o | Xlim-1 | Xl | Up | Induction, but the persistence of an unintended RA effect after the 30 minute exposure and subsequent washes is discussed. | 0007914163; 11112328 | 2 |
| LYN | lyn | Hs | Up | Induction; some differentiation controls. | 1987282; 7512079 | 2 |
| MCL1 | Mcl-1, EAT | Hs, Mm | Up | Induced early in differentiation but with some controls. | 8790944; 8600156; 9655929; 10816607; 11339830 | 2 |
| Mdkp | RIHB, MK | Gg, Mm, Hs | Up | Induction data not good; functional binding site conserved in Hs and Mm; some discussion that it may be indirect in chick. | 0001993066; 0002018506; 8507561; 0007925417; 0007982887; 0007592548; 0009266025 | 2 |
| Meis1 | Meis1 | Gg | Up | Induction (ectopic beads loaded with RA at an apparently physiological dose). | 10952894 | 2 |
| MGP | matrix Gla protein | Hs, Rn | vrs | No good d/t data; potential positive motifs; putative negative binding region. | 2394711; 0001727694; 8214087; 0008319825; 0009122176 | 2 |
| MIG-6q | gene 33 | Rn | Up | Induction. | 0008156927 | 2 |
| MMP11 | stromelysin-3, ST3 | Hs, Mm | Up | No good time data for induction; conserved functional binding site; evidence from receptor knockouts; repression seen under extreme d/t conditions. | 0007657606; 0009111003; 0009824353; 10993903 | 2 |
| Mrg1 | Meis2, Stra10 | Mm, Gg | Up | Induction. | 7649373; 9337137; 10952894 | 2 |
| Mtap7 | E-MAP-115 | Mm | Up | Induction. | 0010837026 | 2 |
| MYC | c-myc | Hs | vrs | Rapid induction in some systems; rapid inhibition on others, but that appears to be indirect; some differentiation controls have been done. | 2414665; 3691668; 0002459072; 2163931; 0008490200; 0008239509; 0008018561 | 2 |
| MYCN | N-myc | Hs, Mm | Dn | Early and rapid suppression; differentiation associated; upstream region responsible has been identified. | 3977910; 3855502; 2405249; 0001565467; 9570357 | 2 |
| NCF1 | p47-phox | Hs | Up | Induction; other NRs. | 2398896; 7578267; 9145335 | 2 |
| NCX | Ncx | Hs, Mm, Rnr | Up | Early induction during differentiation but with some controls; conserved motif necessary for RA effect. | 0010446220 | 2 |
| NES | nestin | Mm, Hs, Rn | Up | Differentiation associated; no good d/t data; conserved binding motif which other NRs also bind. | 8522959; 0009104587; 9057134; 0010222142; 10876035 | 2 |
| Ngfr | LNGFR, p75NTR | Rn, Hs | Up | Induction; a promoter region conferring the RA response has been identified; other NRs. | 1964179; 0001446821; 1325442; 10816607; 10661835 | 2 |
| Nr2c1 | TR2-11 | Mm | Up | No good d/t data; late reporter induction with exogenous RAR and RXR, or during differentiation with endogenous receptors; functional binding site (DR0). | 0010393558; 10807954 | 2 |
| NR2C2 | TR4 | Hs, Mm | Up | Induction. | 0009593676; 0010201524 | 2 |
| NR4A3 | NOR-1 | Hs | Up | Induction. | 9070291 | 2 |
| NRD1 | NRD convertase | Hs | Dn | Induction; specific ligands; no motif found. | 0009049835; 11042131 | 2 |
| NRIP1 | RIP140 | Hs | Up | Induction; upstream region identified. | 11467847 | 2 |
| OXT | OT | Hs, Rn, Bt | Ups | Induction, but d/t data borderline; conserved functional motifs; other NRs. | 0001657967; 0001311087; 0008383287; 0008195142; 0008674853 | 2 |
| Pcp2 | Pcp-2, PCD5 | Mm | Up | Reporter induction; no good d/t data; functional binding site; other NRs. | 0009224660 | 2 |
| PIK3CG | PI3Kγ | Hs | Up | Induction. | 0010392906 | 2 |
| Pkca | PKC | Mm | Up | Induction is relatively rapid (or during differentiation), but appears to be at least partly indirect; functional binding site. | 0002743337; 0001550338; 0010486248; 0010608897 | 2 |
| PLAT | t-PA | Hs | Up | No good d/t data; functional DR5 binding site, but induction may depend on protein synthesis; requirement for Sp1. | 0002542775; 0007706255; 0010452548 | 2 |
| PTAFR | PAFR | Hs, Rn | Up | No good d/t data; functional binding site. | 0008570633; 0009131130 | 2 |
| RAI3 | RAIG3 | Hs | Up | Induction. | 0009857033 | 2 |
| RARRES3 | TIG3, RIG1 | Hs | Up | Induction, but d/t borderline; specific ligands; motifs noted in contig. | 0009843971; 0010687848; 10955811 | 2 |
| RBP4 | RBP | Hs, Mm | Up | No good d/t data; two upstream regions of about 30 bp each, separated by another 30 bp region that apparently functions as an SP1 site, weakly bind various combinations of RARs and RXRs and drive a reporter, however, they contain no obvious classical binding sites. | 0008077297; 0008810324; 11055551 | 2 |
| RDHL | hRDH-TBE | Hs | Up | Induction. | 11304534 | 2 |
| RUNX3 | AML2, CBFA3 | Hs | Up | Early inductiont during differentiation but with some controls; specific ligands. | 0010419474 | 2 |
| S100A7 | RIS-1, psoriasin | Hs | Up | Induction. | 0007715611; 0008931868 | 2 |
| SERPINB2 | PAI-2, plasminogen activator inhibitor 2 | Hs | Up | Induction; single hexamer motif noted but not tested. | 2513217; 0008578452; 0010583214 | 2 |
| Sftpa1 | SPA | Rn | Up | Induction; motif. | 0008944731 | 2 |
| shh | Shh | Gg, Dr, Cj, Mm, Hs | vrs | Regulation rapid in some systems, but little good d/t data; evidence from dietary studies; specific ligands; functional binding site appears not to be conserved; the relationship between Shh and RA and several possible intermediate genes is not at all clear. | 8269518; 7601313; 0008575626; 8625827; 8805369; 0009233805; 0009878825; 9753672; 0010331971; 0010500184 | 2 |
| SLC10A1 | ntcp | Hs, Rnu | Up | No good d/t data; functional binding site. | 8662994; 0010722729 | 2 |
| SLC5A5 | NIS | Hs | Up | Induction, but d/t borderline; specific ligands. | 9398654; 10890895 | 2 |
| Spp1 | osteopontin, bone sialoprotein I, OP | Mm, Gg, Oc, Rn | Up | Induction; additional RA effect at mRNA processing step; other NRs. | 2175918; 8344389; 7746099; 0008702678; 9618139 | 2 |
| Srebf1 | ADD1 | Mm | Up | Induction. | 0009121491 | 2 |
| Star | StAR | Mm, Rn | Up | Induction; an upstream region responsible for a 9-cis inductive effect was isolated but not tested with RA. | 10221765 | 2 |
| STAT1 | STAT1 | Hs, Mm | Up | No good d/t data; binding site (DR0) apparently functional, but with somewhat unusual characteristics; possibly indirect or reliant on RARb synthesis. | 0008631848; 0009092506; 0010597280 | 2 |
| Stra12 | Stra12 | Mm | Up | Induction. | 7649373 | 2 |
| Stra13 | Stra13, D9 | Mm | Up | Induction. | 0008839844; 9284045 | 2 |
| Stra2 | Stra2 | Mm | Up | Induction. | 7649373 | 2 |
| Stra4 | Stra4 | Mm | Up | Induction. | 7649373 | 2 |
| Stra6 | Stra6 | Mm | Up | Induction; evidence from receptor knockouts. | 7649373; 0007644503 | 2 |
| Stra8 | Stra8 | Mm | Up | Induction; evidence from receptor knockouts. | 7649373; 9154799 | 2 |
| Stra9 | Stra9 | Mm | Up | Induction. | 7649373 | 2 |
| STS | STS | Hs | Up | Induction probable but data hard to read; specific ligands; no motif found in published promoter sequence. | 11284723 | 2 |
| Tcfap2c | AP-2.2 | Mm | Up | Early induction during differentiation. | 0008660922 | 2 |
| Tgfb3 | TGF-β 3 | Mm, Gg, Rn | vrs | Usually studied in association with differentiation or growth arrest; induction can be rapid; no motif found; other NRs. | 1964159; 2146270; 1734039; 8385738; 0008557772; 9731743 | 2 |
| Tgfbr1 | TBRII | Hs, Bt | Up | Induction. | 7757990; 9699509 | 2 |
| Tgfbr2 | TGFb type II receptor | Bt | Up | Induction. | 9699509 | 2 |
| THBD | TM | Hs, Mm | Up | A so-called 'late response’ gene; direct induction is possible, although other factors, particularly Sp1, seem to be involved; the response is enhanced by cAMP and blocked by cyclohexamide; specific ligands; RAR and RXR appear to be involved with a conserved DR4, but the involvement of ligand in this complex has been questioned. | 1370608; 1312715; 0008389207; 0008207015; 7878635; 0008918245; 0010565546; 11036068 | 2 |
| Ucp3 | UCP3 | Rn, Hs | vrs | No good d/t data; binding site functional in the presence of MyoD. | 10694373; 11024001 | 2 |
| Wnt8d | mWnt-8, Stra11 | Mm | Up | Rapid induction. | 7649373; 8887323 | 2 |
| Aanat | AANAT | Cj | Dn | No good d/t data. | 0010451022 | 1 |
| ABCB1 | MDR1, mdr3, pgp1 | Hs, Mm, Ma | Up | Induction during differentiation; some differentiation controls; no good t/d data; conserved AP-1 site seems required. | 2573830; 0001661134; 8101511; 0009667638 | 1 |
| Abl1 | c-abl | Mm | Up | No good d/t data; induced during differentiation. | 2458954; 1371335 | 1 |
| Acta1 | α-skeletal actin | Mm | Dn | No good d/t data; other NRs. | 8601621 | 1 |
| Acta2 | α-SM | Mm, Rn, Hs | vrs | During differentiation, growth control, wound healing, or other phenotype change; no good d/t data; specific ligands; probably indirect. | 7728990; 10364073; 11230985; 11319755 | 1 |
| ADAMTS5 | Aggreganase-2 | Bt, Hs, Rn | Up | See ADAMTS4. | 7531436; 0007852317; 8603731; 10395742; 0010403768; 10936450 | 1 |
| ADCYAP1 | PACAP | Hs | Dn | No good d/t data. | 0009285932 | 1 |
| ADCYAP1R1 | PACAP1 (Type I) Receptor | Hs | Dn | No good d/t data. | 0009285932 | 1 |
| Akap12v | SSeCS | Rn | Up | No good d/t data. | 11181072 | 1 |
| AKR1C3 | HAKR e | Hs | Up | No good d/t data. | 0009862446 | 1 |
| Aldh1a1 | ALDH1 | Mm | vrs | No good d/t data; possible induction with low dose but suppression at higher dose; conserved (Hs, Mm, Rn) binding region but no clear motif; probably indirect (C/EBP β). | 10995752 | 1 |
| ALPIw | IAP | Hs | Dn | No good d/t data. | 0010691970 | 1 |
| Ambp | α 1-microglobulin | Rn | Up | No good d/t data. | 0001371972 | 1 |
| App | β-amyloid precursor protein | Rn, Hs, Mm | Up | No good d/t data; delayed induction; motifs in Intron 7 (including one in an Alu) but induction data usually relies on upstream regions only. | 0007500834; 0008714200; 0009121703; 0009748493; 0010727079 | 1 |
| AR | AR | Hs, Rn | vrs | No good d/t data; other NRs. | 1428232; 8022710; 9182860; 10067845 | 1 |
| Ascl1 | MASH1 | Mm, Hs | vrs | No good d/t data; differentiation associated. | 1576967; 10080936; 11414696 | 1 |
| Ascl2 | Mash-2 | Mm | Dn | No good d/t data; decreased during differentiation. | 1576967 | 1 |
| B3GNT5 | β3Gn-T5 | Hs | Up | No good d/t data; induction during differentiation but with some controls. | 8621726 | 1 |
| Bapx1 | NKX3.2, BapX1 | Mm, Gg | Up | No good d/t data. | 0010469600 | 1 |
| BCL2 | Bcl-2 | Hs | vrs | No good d/t data; most studies use differentiating systems, but some controls have been done; at least partly indirect; specific ligands. | 8402688; 8572591; 8642855; 9192771; 10557066; 11181829 | 1 |
| BIRC5 | survivin | Hs | Dn | No good d/t data. | 10698506; 11313272 | 1 |
| Bmp2 | Bmp2 | Mm, Gg, Hs, Dr | vrs | Induction in some systems, but d/t borderline; no good d/t for suppression; generally studied during differentiation, development, or growth inhibition; specific ligands; yeast system; one upstream region conferring small RA effect has been isolated, but no functional binding motif has been found anywhere in the gene; several indirect mechanisms have been discussed, both in up-regulated and down-regulated cases. | 1550961; 8385738; 8119128; 8788040; 0008739045; 9753672; 0009880512; 11054542; 10942599 | 1 |
| Bmp4 | Bmp-4 | Mm, Hs | Dn | No good d/t data; at least partly indirect (Hoxa-1). | 8788040; 10862743; 10942599 | 1 |
| BST1 | CD157 | Hs | Up | No good d/t data; mRNA studies lacking. | 11089918 | 1 |
| CA2 | CA II | Hs, Gg | Up | Induction during differentiation or with exogenous RARs; motif; other NRs (THRa, c-ErbA, VDR); down-regulated by long-term exposure to high RA concentration. | 1700414; 0007916146; 7615086; 0010799323 | 1 |
| Calb1x | Calbindin-D 28k | Rn, Hs, Gg | Up | Late induction; increased mRNA stability; other NRs. | 0008076693; 0008584029; 9773502 | 1 |
| CAMK2A | CaM kinase II, α-CaMKII | Hs, Rn | Up | No good d/t data; promoter region responsible identified. | 0007913411; 8795626 | 1 |
| Camk2d | delta CaM kinase II | Mm | Up | No good d/t data. | 11146121; 11080189 | 1 |
| Camkk1 | CaMKKα | Mm | Up | Rapid induction during differentiation, but no good dose data; cell lines used have dominant negative RARa. | 10560916 | 1 |
| CASP1 | ICE | Hs | Up | No good d/t data; late induction. | 9276475 | 1 |
| Casp3 | caspase 3 | Rn, Hs | Up | No good d/t data. | 10733907; 11464863 | 1 |
| Cbg | CBG | Rn | vrs | No good d/t data. | 0007514032; 8645609 | 1 |
| Ccne1 | cyclin E | Mm | Up | No good d/t data; no significant change reported (but data not shown) in one short-term mRNA study; evidence from transgenics. | 10479451; 11071877 | 1 |
| Cd164y | endolyn, sialomucin | Rn | Up | No good d/t data. | 11181072 | 1 |
| CD44 | CD44 | Hs | vrs | No good d/t data; differentiation associated but some controls. | 7576948; 9525482 | 1 |
| CD58 | LFA-3, CD58 | Hs | vrs | Regulated during differentiation but some controls have been done; mRNA data lacking. | 1706327; 1354203; 10959555 | 1 |
| CD59 | CD59 | Hs | vrs | No good d/t data; differentiation associated. | 7507222; 0009109513 | 1 |
| CDC2 | p34(CDC2) | Hs | Dn | No good d/t data; during differentiation but some controls; at least partly post-translational. | 1751405; 9259311; 9233783; 0010447003 | 1 |
| CDH1 | E-cadherin | Hs | vrs | No good d/t data. | 7984043; 8519658; 9590130 | 1 |
| CDH2 | N-cadherin | Mm, Gg | vrs | No good d/t data. | 0008314004; 10590479; 11414696 | 1 |
| CDH3 | P-cadherin | Hs | Dn | No good d/t data. | 7984043 | 1 |
| Cdh6 | cadherin-6 | Mm | Up | No good d/t data; increased during differentiation; probably indirect (Hoxa-1) at least in some systems. | 0009109513; 10942599 | 1 |
| Cdkn1a | mda-6, p21, WAF1, CIP1 | Mm, Hs, Rn | vrs | No good d/t data; no significant change reported (but data not shown) in one short-term mRNA study; regulated during differentiation or growth arrest; differentiation controls; functional binding motif; knockout evidence; other NRs; probably at least partly indirect. | 7936668; 0008702678; 0008940196; 8895764; 0009490650; 10479451; 0010645889; 11032820 | 1 |
| CHGA | CHGA | Hs | Up | No good d/t data; promoter region conferring RA effect isolated. | 0007576943 | 1 |
| Chgb | Cg B | Mm | Up | No good d/t data; no motif found; probably indirect. | 11014221 | 1 |
| Clta | A4 | Mm | Up | Rapid induction with high RA dose during differentiation in receptor-modified cells. | 0008839844 | 1 |
| CNTFR | CNTF receptor | Hs, Gg | Up | No good d/t data. | 0008989665; 0009488162 | 1 |
| Cntn1 | F3 | Mm | Up | No good d/t data; dispersed half-site motifs; probably indirect (possibly with Hox involvement). | 0009332725 | 1 |
| Col3a1z | α1(III) collagen | Gg | Up | No good d/t data. | 3653521 | 1 |
| Col4a2 | collagen IV (α 2) | Mm | vrs | Slight early decrease followed by larger increase much later; this was an early work and the hybridizing clone was not sequenced; nor was a sequence for either Col4 chain available at the time; the clone was designated α 2 on the basis of estimated weight following in vitro translation; α 1 is discussed as well. | 6310600 | 1 |
| CR1 | CR1 | Hs | Up | No good d/t data. | 10023853 | 1 |
| Cryd1aa | delta 1-crystallin | Gg | Up | Induction of a cross-species transgene in the presence of exogenous RARb; no good time data. | 9216065 | 1 |
| CSF1 | M-CSF, CSF-1 | Hs | vrs | No good d/t data; may be at least partly post-transcriptional (when it is suppressed). | 8217219; 9616179 | 1 |
| CTSB | cathepsin B | Hs | Up | Induction during differentiation; no good d/t data. | 0010534117 | 1 |
| CYBB | gp91-phox | Hs | Up | No good d/t data; may require γ interferon. | 7578267; 9447831 | 1 |
| CYP1A1 | cytochrome P4501A1 | Hs, Rn | vrs | No good d/t data; DR4 binding site drives T3 and RA reporters. | 0008024563; 0007697808; 0010462515 | 1 |
| Cyp3a3 | CYP3A | Rn | Up | No good d/t data. | 0009154443 | 1 |
| CYP4F2 | CYP4F2 | Hs | Up | No good d/t data; specific ligands; functional binding sites; other NRs; possibly RXR.RXR. | 10860554; 11162441 | 1 |
| Dab2 | mDab2 | Mm | Dn | No good d/t data. | 10340473 | 1 |
| DAG1 | dystroglycan α, β | Hs | Dn | No good d/t data; decreased during differentiation. | 0009109513 | 1 |
| Dbx1 | Dbx1 | Mm | vrs | No good d/t data; specific ligands. | 10399918 | 1 |
| dbx1a | hlx-1 | Dr | Dn | No good d/t data. | 9019248 | 1 |
| Dbx2 | Dbx2 | Mm | Up | No good d/t data; specific ligands. | 10399918 | 1 |
| DCT | dopachrome conversion factor, TRP-2 | Mm, Hs | vrs | No good d/t data. | 2107263; 11180971 | 1 |
| DDX1bb | DEAD box protein | Hs | Dn | No good d/t data; decreased during differentiation. | 0009109513 | 1 |
| DDX17 | DEAD box protein p72 | Rn, Gg | Dn | Down-regulated during differentiation; no good d/t data. | 0010718294 | 1 |
| DIO1 | type 1 iodothyronine deiodinase | Hs | Up | No good d/t data; TRE motif can mediate RA regulation. | 8077363; 0009249039; 0009492050 | 1 |
| Dio3cc | D-III, D3 | Rn | Up | Slow induction; other NRs involved (including THRb). | 7525478; 8770927; 10342885 | 1 |
| DPYSL3 | Ulip | Hs | Up | No good d/t datadd; increased during differentiation; the possibility of indirect action has been discussed. | 0009115293 | 1 |
| DSC2 | desmocollin 2 | Hs | Dn | No good d/t data; down-regulated during “apparent” inhibition of differentiation. | 10421061 | 1 |
| DSC3 | desmocollin 3 | Hs | Dn | No good d/t data; down-regulated during “apparent” inhibition of differentiation. | 10421061 | 1 |
| DSG3 | desmoglein 3 | Hs | Dn | No good d/t data; down-regulated during “apparent” inhibition of differentiation. | 10421061 | 1 |
| EMP1 | CL-20 | Hs | Dn | No good d/t data; inhibition during inhibition of squamous differentiation; specific ligands. | 0007499420 | 1 |
| ERBB2 | c-erbB-2 | Hs | Dnee | No good d/t data; during growth inhibition or other phenotypic change. | 9662255; 0009791009; 0010674883 | 1 |
| ERBB3 | c-erbB-3 | Hs | Dnff | No good d/t data. | 0009791009; 0010674883 | 1 |
| ERBB4 | c-erbB-4, HER4 | Hs | Dn | No good d/t data; studied during growth inhibition. | 10383375 | 1 |
| eve1 | eve1 | Dr | vrs | No good d/t data. | 0009879709 | 1 |
| Evx1 | Evx-1 | Mm | Dn | Decreased during differentiation; no good d/t data. | 1971786 | 1 |
| F3 | TF, tissue factor, F3 | Hs | Dn | Many studies involve differentiating systemsgg; suppression rapid in some lines; other NRs; specific ligands; at least partly indirect (several mechanisms have been proposed). | 7949172; 8632672; 9269772; 9585253; 10400422 | 1 |
| FCER2 | CD23 | Hs | Up | No good d/t data; some differentiation controls. | 7682243; 0008877104 | 1 |
| FGF5 | FGF-5 | Mm | Up | Increased during differentiation; no good d/t data. | 2318343; 10557354 | 1 |
| Fgf 9 | FGF9 | Mm | Up | Induced during differentiation; no good d/t data. | 7656983 | 1 |
| FGFR2 | FGFR-2 | Hs | Dn | Suppressed during differentiation; no good d/t data. | 7680553 | 1 |
| FGFR3 | FGFR-3 | Hs | Dn | Suppressed during differentiation; no good d/t data. | 7680553 | 1 |
| FGFR4 | FGFR-4 | Hs, Mm | Dn | Suppressed during differentiation; no good d/t data. | 7680553; 8077293 | 1 |
| FGR | fgr | Hs | Up | Induced during differentiation; no good d/t data. | 1987282 | 1 |
| FKBP1A | FKBP12 | Hs | Up | No good d/t data; increased during differentiation; mRNA data lacking. | 0009472103 | 1 |
| FOLR2 | FR-β | Hs | vrs | No good d/t data; late induction in some leukemic, non-APL lines; some differentiation controls; no motif found. | 11071651 | 1 |
| Fos | c-fos | Rn, Mm, Gg | vrs | Very little good d/t data for mRNA; no significant change reported (but data not shown) in one short-term mRNA study; several indirect mechanisms proposed (including SRE and mRNA stability); other NRs. | 3691668; 2108933; 2163931; 1909429; 0001400313; 1568207; 8336949; 8226882; 0007999013; 7851664; 0010395942; 10479451 | 1 |
| Foxa2 | HNF-3 β | Mm | Up | Delayed induction during differentiation. | 7925656; 9260895 | 1 |
| Fshr | FSH-R | Ss, Rn | vrs | No good mRNA d/t data using RA alone. | 3118982; 0010699459 | 1 |
| Fut4 | CD15, Lewis x, SSEA-1 | Rn | vrs | No good d/t data; generally observed only as a marker; other NRs. | 0001362196; 7905817; 8621726; 9678720 | 1 |
| FXYD3 | RA28 | Hs | Up | No good d/t data. | 0010667226 | 1 |
| Fyn | fyn | Mm, Hs | Up | No good d/t data. | 8643689; 1987282 | 1 |
| GAP43hh | GAP-43 | Hs | Up | Induction (sometimes very rapid) during differentiation; some differentiation controls; requires protein synthesis, at least in some systems. | 1645738; 7649373; 8679712; 11120388 | 1 |
| GATA2 | GATA-2 | Hs | vrs | No good d/t data. | 1370462; 7738198 | 1 |
| Gata4 | GATA-4 | Mm, Rn, Cj | Up | No good d/t data; other NRs; evidence from receptor knockouts; evidence from dietary studies. | 8455608; 0008007990; 7823950; 9986733 | 1 |
| Gata6 | GATA-6 | Mm | Up | No good d/t data; induced in Gata4 −/− animals. | 9256344 | 1 |
| Gck | glucokinase | Rn | Up | No good d/t data. | 1537314; 9220022; 10385401 | 1 |
| Gfra1 | GFRα-1 | Rn | Up | No good d/t data. | 0010751444 | 1 |
| Gfra1 | GFRα-1 | Rn | Up | No good d/t data. | 0010751444 | 1 |
| Gjb3 | connexin31 | Rn | Dn | No good d/t data. | 8806447 | 1 |
| Gpcr13 | H218 | Mm | Dn | Suppressed during differentiation; no good d/t data. | 9521849 | 1 |
| Grasp | GRASP | Mm | Up | Induction (partially inhibited by cyclohexamide). | 10828067 | 1 |
| GRP | GRP | Hs | Up | No good d/t data. | 0009468588 | 1 |
| HCK | Hck | Hs | Up | No good d/t data. | 8018933; 7512079; 8995234 | 1 |
| HNF4A | HNF4α | Hs | vrs | No good d/t data; DR1 binding site, may be RXRE. | 0009792724; 11027556 | 1 |
| HOXC5 | HOX3D | Hs | Up | Delayed induction; motif. | 0001346761 | 1 |
| Hoxd10 | Hoxd-10 | Mm | Dn | Shared regulatory silencing region that binds RARs and COUPs; no good d/t data; brings inappropriate expression when mutated in transgenics. | 0008824591 | 1 |
| Hoxd11 | Hoxd-11 | Mm | vrs | Shared regulatory silencing region that binds RARs and COUPs; no good d/t data; brings inappropriate expression when mutated in transgenics. | 0008824591; 8792611 | 1 |
| Hoxd13 | Hox D13 | Gg, Mm, Rn | Dn | No good d/t data. | 7958440; 8792611; 10633866 | 1 |
| HSD11B2 | 11β-HSD2 | Hs | Up | Induction data at 6 hours “detectable” but not statistically significant. | 10026096 | 1 |
| Hsp86-1 | HSP86, HSP90, HSPCA | Mm, Hs | vrs | Up or down during differentiation or apoptosis; regulation within hours in some cases; some differentiation controls; induction, at least, is thought to be independent of RA. | 2806771; 1655528; 8612676; 11146166; 10718371 | 1 |
| ICAM1 | ICAM-1 | Hs, Rn | Up | No good d/t data; late induction; functional binding site (and functional GAS sites); may be secondary to calmodulin, CaM kinase II, or other activity. | 0001983003; 0001680399; 0007914515; 0007913411; 0007737364; 0007647034; 0007913411; 0010411124 | 1 |
| ICAM3 | CD50, ICAM-3 | Hs | Up | No good d/t data for mRNA. | 9497494; 11261782 | 1 |
| Igf1r | IGF-IR | Rn | Up | No good d/t data; other NRs. | 9048627 | 1 |
| IGFBP2 | IGFBP-2 | Hs | vrs | No good d/t data. | 0001382963; 0008640300 | 1 |
| IGFBP3 | IGFBP-3 (42–46kD) | Hs, Bt | vrs | Increase in most cases, but late decrease in Bt cells and at extreme dose/time points in Hs cells; associated with growth inhibition; specific ligands; early, rapid increase appears to require protein synthesis. | 0001382963; 0008620495; 0008655603; 0009153223; 0010580834; 0010364250 | 1 |
| IGFBP5 | IGFBP-5 | Hs, Rn | vrs | No good d/t data; generally decreased, but there may be an opposing increase in mRNA stability. | 0007536661; 0008603611; 0009368678 | 1 |
| IL6 | IL-6 | Hs | Dn | No good d/t data. | 0010704257; 10785230 | 1 |
| IL6R | IL-6R | Hs | Dn | Repressed during inhibition of proliferation; no good d/t data. | 0002033252; 0007949175 | 1 |
| INHBA | Activin A | Hs | vrs | No good d/t data. | 1690989; 8774352 | 1 |
| INSii | proinsulin, insulin | Rn, Hs | Up | No good d/t data; there is a binding site in the uniquely Hs insulin-linked polymorphism. | 1537314; 0007639703; 0009260196 | 1 |
| ITGAL | CD11a | Hs | Up | No good d/t data; some differentiation controls. | 7512079; 8774361 | 1 |
| ITGAM | CD11b, MAC-1 | Hs | vrs | Motifs; no good d/t data; some differentiation controls; specific ligands; other NRs. | 0001347945; 7512079; 8025272; 0010704061; 11426618; 11339831 | 1 |
| Itgav | Integrin α v, vitronectin receptor, CD51 | Mm, Hs, Gg, Oc | Up | No good d/t data. | 1939209; 7529599; 0008891892; 10520221 | 1 |
| ITGB2 | CD18 | Hs | Up | No good d/t data; motifs. | 2901419; 0001346252; 9337080; 10641747 | 1 |
| Itgb4 | β 4 integrin | Mm | vrs | No good d/t data. | 0008287622; 0008875079 | 1 |
| Jun | c-jun | Mm, Rn | Up | Rapid induction probably indirect; no good d/t data for suppression. | 1963081; 0001851295; 0001310930; 8670250; 0009436983; 0010395942; 10479451 | 1 |
| JUNB | jun-B | Hs, Mm | Up | No good d/t data; some differentiation controls; report (data not shown) of no RA effect under low-dose, short-term conditions. | 0001667479; 2113273; 10479451 | 1 |
| KAI1 | CD82 | Hs | Up | No good d/t data; induced during differentiation. | 10630309 | 1 |
| KCNH2 | HERG | Hs | Up | No good d/t data; induced during differentiation. | 9535729; 10413451 | 1 |
| Kitl | c-kit ligand, stem cell factor, SCF | Mm, Hs | Up | No good d/t data. | 7537079; 8874749; 9827903; 11205272 | 1 |
| KLK7 | SCCE | Hs | Dn | No good d/t data; mRNA data lacking. | 8105613 | 1 |
| KRT10 | K10 | Hs, Oc | Dn | No good d/t data; region that responds to RA identified; RAR (only) binding demonstrated; hexamer motifs. | 1712634; 1375251; 1284070; 10542138 | 1 |
| KRT13 | K13 | Hs, Oc, Rn, Mm | Up | No good d/t data; induced during differentiation, but some differentiation controls have been done; potential response element found not to be active; AP-1 regulation; specific ligands. | 6205395; 2470609; 7687243; 0007525098; 8634095; 0008853895 | 1 |
| KRT14 | K14 | Hs, Oc | vrs | No good d/t data; associated with differentiation (or inhibition of differentiation); upstream region responsible for RA effect (suppression) identified; in vitro RAR binding; AP-1 regulation; other NRs. | 1700022; 1711202; 1375251; 0001281867; 10713177 | 1 |
| KRT16 | K16 | Hs, Oc | vrs | During differentiation (or inhibition of differentiation); no good d/t data; upstream region responsible for RA effect identified. | 2470609; 1711202; 1375251; 8977666 | 1 |
| KRT17 | K17 | Hs | Up | No good d/t data; an upstream cluster of hexamers that can bind RAR (weakly) and suppress a CAT reporter has been found; other NRs. | 1708801; 8977666; 0009326392 | 1 |
| KRT2A | K2e | Hs | Dn | No good d/t data. | 10692107 | 1 |
| KRT3 | K3 | Hs, Oc | Dn | No good d/t data; upstream region responsible for RA effect identified. | 1375251 | 1 |
| KRT6Ajj | K6 | Mm, Hs | vrs | Recent duplications make it difficult to be sure which K6 gene is being studied in many papers; there appear to be significant difference between RA effects in vitro and in vivo, with up-regulation perhaps the most likely in vivo effect; both positive and negative motifs have been proposed; AP-1 regulation; no good d/t data in vivo. | 2439609; 1711202; 0007682522; 0007545670; 0009326392; 9790766; 10887174 | 1 |
| KRT7 | K7 | Hs | Up | No good d/t data. | 2459129; 7505756 | 1 |
| Laptm5 | E3 | Mm | Up | Rapid induction with high RA dose during differentiation in receptor-modified cells; no good d/t data for other cells; binding motif in region responsible. | 0008839844 | 1 |
| Lep | leptin, ob | Rn, Hs | Dn | No good d/t data; other NRs. | 9659286; 9514867; 10381155; 10902807; 11479138; 11369444 | 1 |
| Lgals1 | 14.5-D lectin, L-14 | Mm, Hs, Rn | vrs | Differentiation associated; no good d/t data; no likely binding site found. | 2555043; 8135794; 7954433; 9865605; 10760565 | 1 |
| Lgals3 | 34-kD lectin, L-34 | Hs, Mm | vrs | Differentiation associated; no good d/t data. | 2555043; 2537146; 9865605 | 1 |
| LGALS7 | Galectin-7 | Hs | Dn | No good d/t data. | 7729568 | 1 |
| LOR | Lorcrin | Hs | Dn | No good d/t data. | 0001710017; 0002007780; 0001378029; 0007516397 | 1 |
| LPA | apolipoprotein(a), apo(a) | Hs, Mf | Dn | No good d/t data; motif. | 0009299449; 0009535807; 0010423167 | 1 |
| Ltf | lactoferrin | Mm | Up | No good d/t data for RA; induction at 6 h with 9-cis; functional binding site; other NRs. | 8113151; 0007623814; 0009828118; 0010505667 | 1 |
| Mapk1 | Erk2 | Hs, Mm | Upkk | No good d/t data for mRNA; region at least partially responsible for RA effect identified; no apparent response element. | 0009261178; 9679985; 10548434 | 1 |
| MAX | max | Hs | vrs | Delayed induction in some studies; no change in others. | 0008239509; 8134128; 8570225; 0009804832 | 1 |
| Mc1r | melanocyte-stimulating hormone receptor | Mm, Hs | vrs | No good d/t data for mRNA; specific ligands. | 0002265702; 0008168086; 9610863 | 1 |
| Meox1 | Mox1 | Mm | Up | Late induction during differentiation. | 7649373 | 1 |
| MLN64ll | MLN/CAB1 | Hs | Dn | Data not shown. | 11146166 | 1 |
| MME | CD10, NEP | Hs | vrs | No good d/t data; differentiation associated change; mRNA data lacking. | 7528753 | 1 |
| MMP13 | MMP-13 | Bt, Ss, Hs | vrs | No good t/d data. | 10548534; 10429942 | 1 |
| MMP2 | gelatinase A | Hs, Gg | vrs | Early studies of enzyme activity (not mRNA) showed a decrease with high dose/long exposure conditions; later studies have shown late increases; upstream region conferring RA effect identified; probably indirect. | 6279711; 8314305; 0008858101; 9664142; 9407317; 0010329442 | 1 |
| MSX1 | Msx-1 | Mm, Hs, Gg | vrs | No good d/t data; motif in Mm not Hs; required binding region for induction in Hs; possibility of indirect action discussed. | 0007916326; 0007866431; 0007650517; 0009045990; 9870533 | 1 |
| Msx2mm | Msx-1 | Gg, Cj | Dn | No good d/t data; whole animal evidence for RA effect. | 0001685987; 0007650517; 0009045990 | 1 |
| Mt3 | MT-3 | Mm | Up | No good d/t data. | 0010712606 | 1 |
| MUC2 | MUC2 | Hs, Mf | vrs | Induced or inhibited, but no good d/t data; down-regulated following maintenance in retinoid- depleted culture; specific ligands. | 0008179918; 0008997274; 0009870916; 0010024510; 11200589 | 1 |
| Muc3 | RMUC176 | Rn | Up | No good d/t data. | 0008297336 | 1 |
| MUC5AC | MUC5AC | Hs, Rn | Up | No good d/t data; down-regulated after maintenance in retinoid-deprived culture; down-regulated in vitamin A deficient animals; specific ligands. | 0008997274; 0009870916; 0010024510; 11200589; 0010634605 | 1 |
| MUC5B | MUC5B | Hs | Up | No good d/t data; specific ligands; down-regulated in retinoid-depleted culture. | 0009870916; 0010024510; 11200589 | 1 |
| MYBL2 | B-myb | Hs | Dn | Inhibition during differentiation; no good d/t data. | 8598228 | 1 |
| MYCL1 | L-myc | Hs | vrs | No good d/t data for repression; induction may be rapid, but data unclear; induction blocked by cyclohexamide. | 8123593; 8934535; 0010074929 | 1 |
| NCF2 | p67-phox | Hs | Up | No good d/t data; other NRs. | 7578267; 9145335; 9447831 | 1 |
| NDRG1 | RTP, Drg1, Ndr1 | Hs | Up | Induced during differentiation; no good d/t data. | 0010395947 | 1 |
| Ngp | F1 | Mm | Up | Rapid induction with high RA dose during differentiation in receptor-modified cells. | 0008839844 | 1 |
| NME1 | nm23-H1 | Hs | Up | No good d/t data. | 0010664247 | 1 |
| NOS1 | n-NOS, nNOS | Hs, Mm | Up | No good d/t data; induced during differentiation. | 8929985; 10820202 | 1 |
| Nos2 | iNOS, NOS2 | Hs, Rn | vrs | No good d/t data. | 9635256; 0010772914 | 1 |
| NOS3 | eNOS | Hs | Dn | Down-regulated late in differentiation; no good d/t data. | 9635256 | 1 |
| Notch1 | Notch-1 | Mm | vrs | No good d/t data. | 7615640; 11414696 | 1 |
| NPY | NPY | Hs | Dn | No good d/t data; no motif found. | 10854907 | 1 |
| NR3C1 | GR | Hs, Mm | vrs | No good d/t data (or d/t conditions not described). | 6611455; 8339256; 7994082; 7854351; 11146166 | 1 |
| NR4A2 | Nurr1 | Hs | Up | Data hard to interpret at early time points. | 9070291 | 1 |
| Nr6a1 | GCNF, RTR | Hs, Mm | vrs | Transient induction followed by repression during differentiation; no good d/t data. | 9134503; 0009563832; 10524192 | 1 |
| Ntrk2 | Trkb | Rn, Hs | Up | Induced during differentiation; no good d/t data. | 7988722; 0008817533 | 1 |
| NTRK3 | TrkC | Hs | Up | Induced during differentiation; no good d/t data. | 0008817533 | 1 |
| Olr1nn | LOX-1 | Rn | Up | No good d/t data; rapid induction with high dose. | 11181072 | 1 |
| PCDH11 | PCDHX | Hs | Dn | No good d/t data (but only a qualified claim is made in the paper). | 11003707 | 1 |
| PCDH22 | PCDHY | Hs | Dn | No good d/t data. | 11003707 | 1 |
| Pdgfrb | PDGF receptor β | Mm | Up | No good d/t data. | 2155144; 8180134 | 1 |
| PECAM1 | PECAM-1, CD31 | Hs, Mm | vrs | Motifs; regulated during differentiation, but some controls have been done; no good d/t data. | 0008955189; 9678720; 10830620; 11397002 | 1 |
| PLAU | u-PA | Hs, Bt, Mm | Up | Induction by RA alone is slow or during differentiation; in other assays, RA appears ineffective by itself; no motif found; probably indirect. | 0008491555; 0008385052; 0008404615; 0009560322; 0010361124 | 1 |
| Pou4f 2 | Brn-3.2 | Mm | Dn | No good d/t data for RA alone; inhibition rapid if cAMP is present. | 0007904822 | 1 |
| Pou5f1 | Oct-3, Oct-4, Oct3/4 | Mm, Hs | vrs | No good d/t data; indirect repression through the upstream 1.2 kb region (no RARE motif); reporter induction through proximal RARE motif; indirect repression through proximal RARE motif; indirect repression through the upstream 2 kb region; other NRs. | 0001915274; 0008289783; 0008289793; 0008152920; 0007823919; 0008832901; 0008631309; 0010512201; 0010692469 | 1 |
| PPP3CA | calcineurin A | Hs | Up | No good d/t data; increased during differentiation; mRNA data lacking. | 0009472103 | 1 |
| PPP3CB | calcineurin B | Hs | Up | No good d/t data; increased during differentiation; mRNA data lacking. | 0009472103 | 1 |
| PRAM-1oo | PRAM-1 | Hs | Up | No good d/t data in non-APL cells. | 11301322 | 1 |
| PRKCB1 | PKC β 1 | Hs, Rn, Mm | vrs | No good d/t data for mRNA; some differentiation controls; other NRs. | 3422643; 1868031; 0001550338; 7961696; 9145335; 8732669; 9486851 | 1 |
| PRKR | p68 kinase | Hs | Up | No good d/t data. | 9393879 | 1 |
| PRLR | PRL-R | Hs | Dn | No good d/t data for RA, but protein synthesis not required; specific ligands; rapid reduction with 9-cis. | 0009888458 | 1 |
| PRNP | PrP | Hs | vrs | No good d/t data. | 7984043; 9473220 | 1 |
| PTEN | PTEN | Hs | Up | No good d/t data; increased during differentiation but some controls have been done. | 11290607 | 1 |
| Ptgds | PGDS | Rn | Up | No good d/t data; contains a functional TRE that can act as an RARE in vitro. | 0009582446; 9579690; 10650953 | 1 |
| Ptgs1 | Cyclooxygenase-1, COX-1, PGHS1 | Mm, Rn, Hs | vrs | No good d/t data; induction (when it occurs) may be blocked by cyclohexamide. | 7851378; 8967521; 8948503; 11299304 | 1 |
| PTGS2 | TIS10, COX-2, PGHS2 | Hs, Mm, Rn | vrs | Modest induction using RA or platelet-activating factor alone; stronger induction with RA + PAF; binding region for RA + PAF activation contains no obvious motif, but no site for independent RA activity sought elsewhere in the gene; most studies use long incubation periods or high doses. | 0008202477; 7851378; 8967521; 8948503; 9569236 | 1 |
| Pth | Pth | Bt | Dn | No good d/t data; other NRs. | 8377475; 0008113407 | 1 |
| Pthr | Pthr | Rn, Mm | vrs | Delayed suppression; no good time data for induction; a DR1 is involved in induction but it is not sufficient; other NRs. | 0001660713; 0009792954; 0010406468 | 1 |
| PTK2 | focal adhesian kinase, FAK | Hs | vrs | No good d/t data for mRNA; various non-transcriptional effects have been demonstrated. | 9566310; 9590130; 9989778; 11369141 | 1 |
| PTMA | ProT α | Hs | vrs | No good d/t data or data not shown. | 8416800; 11146166 | 1 |
| PTPN13 | CD95 | Hs | Dn | No good d/t data. | 0009792441 | 1 |
| Rai2 | RAI2 | Mm, Hs | Up | No good d/t data in Mm; Hs ortholog proposed only by analogy. | 0008314004; 0010049581 | 1 |
| RARRES1 | TIG1 | Hs | Up | No good d/t data; tested only with synthetic retinoids and specific ligands. | 0008601727 | 1 |
| RARRES2 | TIG2 | Hs | Uppp | No good d/t data; tested only with synthetic retinoids and specific ligands. | 0009204961 | 1 |
| Rbp2 | CRBPII | Rn, Mm, Hs | Up | Induction controversial; motifs; no good d/t data; other NRs; possibly an RXR.RXR system; physiological relevance of RA questioned. | 0001651173; 0008288643; 0009040537 | 1 |
| RET | ret | Hs, Rn | Up | Induced during differentiation; no good d/t data; motif not found. | 1766678; 7867726; 0009426223; 0009843911; 0010751444 | 1 |
| Rho | Rod-specific opsin, rhodopsin, Rh1 | Mm, Dr, Dm | Up | No good d/t data; evidence from transgenics; evidence from dietary studies. | 8681798; 8917585; 8994352; 10711716 | 1 |
| RNPEP | aminopeptidase-B | Hs | Dn | Late increase; specific ligands. | 0009049835 | 1 |
| Rrg1 | NN8-4AG | Mm | Up | Induction seems to occur rapidly but RA activity is blocked by protein synthesis inhibitors (9-cis activity is not); motif binds RAR.RXR and RXR.RXR; RA induction is probably at least partly indirect. | 0008754834 | 1 |
| RTN1 | NSP-A | Hs, Rn | Up | No good d/t data. | 9560466 | 1 |
| RTN3 | NSP-C | Hs, Rn | Up | No good d/t data. | 9560466 | 1 |
| Rxra | RXR α | Mm | Upqq | No good d/t data; other NRs; AP-1 regulation; message may be superinduced by cyclohexamide. | 8269997; 8806431; 0008940178; 10403834; 0009717711 | 1 |
| S100A8 | MRP-8 | Hs | Dn | No good d/t data; tested only with synthetic retinoids. | 0010319995 | 1 |
| SAG | arrestin | Hs, Mm | Up | No good t/d data; partially conserved motif; the Mm site binds RAR.RXR, but the Hs site is “inefficient”; the Mm site drives a heterologous reporter construct, but the Hs site (which is identical to the Bt site) does so only poorly; may be primarily COUP regulation. | 0007708064; 9068616 | 1 |
| SALFrr | SALF | Rn | Up | No good d/t data; rapid induction with high dose. | 11181072 | 1 |
| SCD | SCD | Hs | Up | No good d/t data; specific ligands. | 11397803 | 1 |
| SCYA2 | MCP-1 | Hs, Rn | vrs | No good d/t for RA but rapid induction with 9-cis; other NRs; suppression, when it occurs, is probably through AP-1. | 7919389; 10479651; 11274229 | 1 |
| SDC2 | HSPG | Hs | Up | No good d/t data; increased during differentiation. | 0009109513 | 1 |
| SELL | L-selectin | Hs | Dn | No good d/t data. | 0010704061 | 1 |
| SERPINC1 | antithrombin III | Hs | Up | No good d/t data; motifs are responsive to RXRs and THR; both T3 and RA induce in some systems. | 8192147; 7531260; 0008761481 | 1 |
| SERPINE1 | PAI-1, plasminogen activator inhibitor 1 | Hs | vrs | Induced during differentiation; short term studies report no effect. | 0001905574; 1908141; 0001935958; 0008491555 | 1 |
| SFTPC | SP-C | Hs, Rn, Mm | vrs | No good d/t data; possible mRNA stability effect. | 0008404646; 0008944731; 9458794 | 1 |
| Slc18a3 | VAChT, vesicular acetylcholine transporter | Mm, Rn, Hs | Up | No good d/t data. | 0007673184; 7616258; 0009237624; 10960602; 11306187 | 1 |
| Slc2a2 | GLUT 2 | Rn | Up | No good d/t data; other NRs. | 11494305 | 1 |
| Slugh | Slug | Gg | Dn | No good d/t data; possibly indirect (TGFb2 signaling is involved in some cases). | 9303343; 10864463 | 1 |
| SOD2 | MnSOD | Hs, Rn | Up | Late increase in protein; mRNA studies (using RA alone) are lacking. | 10702810 | 1 |
| Sox9 | SOX9 | Mm | Up | No good d/t data. | 0010753864 | 1 |
| SP100 | Sp100 | Hs | Up | No good d/t data in non-APL cells. | 9393879 | 1 |
| Sparc | SPARC, osteonectin | Mm, Gg | Up | Slow (or differentiation associated) induction; evidence from receptor knockouts. | 1310471; 1584226; 8344389; 0008105479 | 1 |
| SPN | CD43 | Hs | Up | No good d/t data; motifs. | 0009174604 | 1 |
| SPRR1Bss | Spr1, cornifin | Hs, Mf, Oc | Dn | No good d/t data; during differentiation or growth arrest; specific ligands; other NRs. | 1627333; 7769256; 8631988; 8950452; 10615070 | 1 |
| SULT2B1tt | cholesterol sulfotransferase | Oc | Dn | mRNA studies lacking. | 3477542 | 1 |
| SUPT4H1 | SUPT4H | Hs | Up | No good d/t data; increased during differentiation. | 0009109513 | 1 |
| TAF2S | TF CA150 | Hs | Up | Data not shown. | 11146166 | 1 |
| TAT | TAT | Rn | vrs | Down-regulation, when it occurs, may be due to decreased mRNA stability; no good d/t data in either direction; other NRs. | 1350056; 0008100575; 7734399; 0009449205 | 1 |
| Tcf1 | HNF-1 α | Mm, Hs | Up | Induced late in differentiation; RXR.RXR binding site. | 2065662; 11027556 | 1 |
| Tcf2 | HNF-1 β | Mm | Up | Induced late in differentiation. | 2065662; 7649373 | 1 |
| TFAP2A | AP-2 | Hs | Up | No good d/t data; upregulated during differentiation; no motif found up to −1.7 kb. | 0003063603; 0002482225; 0008190633; 0008687453 | 1 |
| TFRC | CD71, TfR | Hs | Dn | No good d/t data; mRNA stability may be involved in some systems; reduction during differentiation or growth arrest. | 6573952; 2702640; 2404770; 9491782 | 1 |
| TGFA | TGF-α | Hs, Mm | vrs | Regulated during differentiation (or growth arrest) but some controls have been done; upstream region conferring increased expression in vitro identified; no motif found; no good d/t data for RA but suppression can be rapid for synthetics; specific ligands; other NRs. | 3215396; 2087681; 0001922084; 7536865; 8619789 | 1 |
| TGFB1 | TGF-β 1 | Hs, Rn | vrs | No good d/t data; suppression (when it occurs) is probably through AP-1; no RARE found; other NRs; some differentiation controls have been done. | 2909528; 1848114; 1334692; 0008264664; 0008557772 | 1 |
| Tgfb2 | TGF-β 2 | Mm, Hs, Gg | Up | Induction but d/t borderline; possible mRNA stability effect; upstream region responsible for RA effect probably identified; no RARE found; evidence of other transcription factor changes following RA treatment; specific ligands; other NRs; some differentiation controls have been done. | 2519621; 2084113; 1734039; 7654367; 0008557772; 0009153223 | 1 |
| Tgm1 | TGase K, TGase1 | Oc, Hs, Rnuu | Dn | No good d/t data; decreased during differentiation; gene can be induced in vitro by RA; AP-1 and AP2 response elements; intronic negative DR5 alluded to. | 2876994; 1356818; 1355099; 0008097865; 8537408; 10321835 | 1 |
| Th | TH | Rn | Up | No good d/t data. | 0008522994 | 1 |
| Thrsp | S14 | Mm, Rn | Up | No good d/t data; other NRs. | 0001322331; 0007997231; 0010187832 | 1 |
| Tnc | Tn-C | Mm, Rn, Hs | vrs | No good d/t for increase; rapidvv reduction possible; other NRs. | 8528505; 10502285; 10078937; 10651229 | 1 |
| TOP2Aww | TopoII | Hs | vrs | No good d/t data; generally studied in differentiating systems; probably indirect. | 7954372; 9763571 | 1 |
| TRA1 | gp96 | Hs | Up | No good d/t data. | 9641219 | 1 |
| Trpm2 | Sgp-2, clusterin | Rn | Dn | No good d/t data; motif. | 1350056; 0009547504 | 1 |
| Tshb | TSH β | Rn, Mm | Dn | No good d/t data; dietary evidence; upstream binding region responsible for RA effect identified and found distinct from T3-responsive region; possibly 9-cis, RXR system; evidence from transgenics. | 0007835286; 0009296372; 10880050 | 1 |
| Tyr | tyrosinase | Mm | vrs | No good d/t data for mRNA; motifs that drive reporter induction identified; other NRs. | 6260817; 2983883; 2107263; 0007620342 | 1 |
| Ucp2 | UCP2 | Rn | Dn | No good d/t data. | 10694373 | 1 |
| VDR | VDR | Hs | Up | No good d/t data directly implicating an undiluted RA/RAR.RXR response; two regions drive reporters; autoregulation (potentially involving retinoid receptors); possibly indirect. | 0009212063; 0010446999; 10919269 | 1 |
| Vegfc | VEGF-C | Mm | Dn | No good d/t data. | 11306173 | 1 |
| VIM | vimentin | Hs, Mm | vrs | No good d/t dataxx; late suppression (or induction) associated with differentiation or cell-cycle arrest; often observed primarily as a marker; no motif found; AP-1 involvement likely at least in some cases. | 3467175; 2447102; 1352781; 0007790400; 0010631814; 11146166 | 1 |
| VIPR1 | VIP1 receptor, VIPR1, PACAP2 (Type II) receptor | Hs | Dn | No good t/d data; possibly a motif.yy | 0007708752; 0009285932; 0009809989; 11150643 | 1 |
| Wnt1 | Wnt-1 | Mm | vrs | No good d/t data; regulated during differentiation or development; region conferring RA effect in vitro isolated but its relevance to at least some in vivo systems has been questioned. | 8441400; 7925022; 8626038; 9636087; 11414696 | 1 |
| Wnt3a | Wnt-3a | Mm | Dn | No good d/t data, although inhibition may be rapid; evidence from receptor knockouts. | 0009882496; 10473117 | 1 |
| WT1 | wt1 | Hs, Mm | vrs | No good d/t data; regulated during differentiation, but some controls have been done. | 8142654; 9040935 | 1 |
| X17Czz | X17C | Xl | Up | No good d/t data. | 0008861094 | 1 |
| ZNF42 | MZF-1 | Hs | Up | No good d/t data; differentiation associated; region containing motifs can drive a reporter. | 0001860835; 0008845378 | 1 |
| Znfn1a1 | Ikaros | Mm | Up | No good d/t data. | 11092879 | 1 |
| ADAMTS4aaa | Aggrecanase | Bt, Rn, Hs | Up | No good d/t data; many papers measure enzymatic activity only, so the gene(s) responsible are not clear; probably indirect. | 7531436; 0007852317; 8603731; 10395742; 10936450 | 0 |
| Adh1 | Adh-1 | Mm | – | No mRNA effect; no site found; possibly based on early confusion about the RA inducibility of the Hs gene previously known as ADH1. | 0008018987 | 0 |
| Afp | α-fetoprotein | Rn, Hs | Up | Delayed induction during differentiation; functional binding sites; some question about whether regulation is primarily by RXRs; other NRs; probably indirect although the –6327 site may mediate direct regulation. | 0001379951; 0007528016; 0007525384; 0007512261; 0008945636; 0009792724; 0010025664 | 0 |
| Agc | Aggrecan | Bt, Rn, Hs | vrs | Probably indirect. | 8492742; 9779827; 0010753864 | 0 |
| Agtr1a | angiotensin II type 1 receptor | Rn | Dn | Indirect. | 0010642314 | 0 |
| AHR | AhR | Hs | Dn | A normal increase during differentiation is inhibited by long-term, continuous RA; short-term exposure during differentiation has no effect; some differentiation controls; probably indirect. | 8950195 | 0 |
| Arhgap5bbb | p190 GAP-associated protein | Rn | Up | Dose and time unclear, but protein synthesis required; probably indirect. | 10667225 | 0 |
| ARNT | ARNT | Hs | Dn | A normal increase during differentiation is inhibited by long-term, continuous RA (1 μM); short-term RA exposure during differentiation has no effect; probably indirect. | 8950195 | 0 |
| Atp1a3 | Na,K-ATPase | Rn | Up | No good d/t data; probably indirect. | 0009925375 | 0 |
| BGLAP | osteocalcin | Hs, Rn, Mm | Upccc | Conflicting gene modulation data; motif (VDRE/ AP-1) drives heterologous promoter and binds RAR; induction, when observed, is probably indirect, possibly through the induction of Srebf1 or through VDR.RAR or VDR.RXR dimers. | 0002159384; 1820970; 0008395017; 0008466530; 8382933 | 0 |
| BLR1 | Blr1 | Hs | Up | Induction during differentiation but some controls; probably indirect. | 10640427; 11211936 | 0 |
| Bmp7 | BMP-7 | Gg, Hs | Up | Probably indirect (protein synthesis). | 0009621899; 11032177 | 0 |
| BTK | BTK | Hs | – | Motifs; no other evidence. | 7927535 | 0 |
| Cal1ddd | CT, CGRP | Rn | Dn | Long treatment required; probably indirect. | 0001569964; 0008413210; 8061571; 9057102 | 0 |
| CCND3 | cyclin D3 | Hs, Mm | Dn | Reduced during growth arrest or differentiation; no good d/t data; no significant change reported (but data not shown) in one short-term mRNA study; evidence from receptor knockouts; probably indirect. | 9260897; 0009806360; 10479451 | 0 |
| Cdrap | CD-RAP | Bt, Mm, Rn, Hs | Dn | Indirect. | 8621736; 9097023; 0009478951; 10320524 | 0 |
| Col1a1 | α 1(I) collagen | Mm, Rn, Hs | vrs | No good d/t data; other NRs; putative response element (a DR37 or a single hexamer) shown to be spurious; probably indirect. | 3919954; 2915650; 0010729205; 2019574; 7918630; 7988442; 0009077477 | 0 |
| Col1a2 | α 2(I) collagen | Mm, Hs, Gg | vrs | No good d/t data; regulation does not seem to be through the identified motif (an unusual DR6); probably indirect. | 3919954; 2987306; 1429872; 0010729205; 3653521 | 0 |
| Col4a1 | collagen IV (α 1), α 1(IV) | Mm, Hs, Bt | Up | No good d/t data; now thought to be indirect. | 0002981185; 0002842348; 0002327791; 9451807 | 0 |
| COL7A1 | type VII collagen | Hs | Dn | No good d/t data; probably indirect. | 9130597 | 0 |
| Cp | ceruloplasmin | Rn | Upeee | No good d/t data; probably indirect (protein synthesis). | 11181072 | 0 |
| CRH | corticotropin-releasing hormone | Hs | Up | Indirect. | 0010446900 | 0 |
| CSF1R | c-fms | Hs | Up | Induction; no motif found in the region sufficient to impart RA inducibility; regulation attributed to AP-1.RAR. | 0010554038 | 0 |
| CTNNB1 | β-catenin | Hs | vrs | Probably indirect. | 8754749; 9414661; 10607566 | 0 |
| CTSD | cathepsin D | Hs | Up | Probably indirect. | 0007547509; 0008639464 | 0 |
| CTSG | cathepsin G | Hs | Dn | Probably indirect. | 8558945 | 0 |
| CTSL | cathepsin-L | Rn | Up | Delayed induction; probably indirect (protein synthesis). | 11181072 | 0 |
| Cyp7a1 | CYP7A | Rnfff, Mm | vrs | No good d/t data; largely transfection, cotransfection, or dietary studies; conserved binding motif, but RA response may not be conserved; many other NRs; probably indirect (possibly through RXR.LXR and FXR.RXR). | 8656080; 0008753804; 0008831673; 0009799805; 10968783 | 0 |
| DEFA1 | promyelocytic defensin-1 | Hs | Up | Probably indirect. | 0009535850 | 0 |
| EDN1 | ET-1 | Hs | Dn | Probably indirect. | 0009809984 | 0 |
| ENPP2 | ATX | Hs | Up | No good d/t data; requires protein synthesis; probably indirect. | 11346880 | 0 |
| Etnmg1 | ETnMG1 | Mm | Dn | Repression probably due to decreased mRNA stability. | 8863732 | 0 |
| Evx2 | evx2 | Dr, Mm | vrs | No good d/t data; probably indirect (Hoxa-1). | 0009879709; 10942599 | 0 |
| FACL2 | acyl-coA synthase, ACS | Hs, Rn | Up | Probably indirect; specific ligands. | 0010777552 | 0 |
| Fasn | FAS | Rn | vrs | No good d/t data; other NRs; probably indirect. | 6164877; 7537465; 0009191201; 9070250; 9510066; 0009770474 | 0 |
| Fbp1 | Fru-1,6-P2ase, FBPase | Mm, Hs | Up | Slow induction during differentiation; no RA regulation seen in whole animal study; binding motif (DR3) is also a VDRE; other NRs; probably indirect. | 9202079; 9556208; 0010731708 | 0 |
| Fgf1 | acidic FGF | Mm | Up | Induced during differentiation; indirect. | 2544608 | 0 |
| Fgf 2 | bFGF, basic FGF | Mm, Cf, Bt | vrs | No good d/t data; differentiation associated; specific ligands; probably indirect. | 2544608; 10607884; 11230116 | 0 |
| Fgf 3 | FGF-3 | Mm | Up | Induced during differentiation; indirect. | 8265348; 10358083 | 0 |
| FGF4 | K-FGF | Hs, Mm | Dn | Suppressed during differentiation; indirect. | 2009969; 0001723621; 8844688 | 0 |
| Fosl1 | Fra-1 | Mm, Hs | Up | Induction, probably indirect. | 10217407 | 0 |
| FSCN2 | Retinal fascin | Hs | – | Motif; no other evidence. | 10783262 | 0 |
| Gja1 | connexin43, Cx43 | Mm, Hs, Rn | Up | Other NRs; probably indirect. | 0002177604; 0001327514; 7954877; 0007720192; 8941706; 9428648; 10192774 | 0 |
| GRIN1 | NMDAR1 | Rn, Hs | Up | No good d/t data; probably indirect. | 8866697; 9219948 | 0 |
| Grnggg | Epithelin | Rn | Up | No good d/t data; probably indirect (protein synthesis). | 11181072 | 0 |
| Gsc | goosecoid | Xl, Dr, Mm | Dn | No good d/t data; generally studied in teratogenicity experiments; specific ligands; no motif found; probably indirect. | 1684739; 7605750; 9207233; 10512193 | 0 |
| Gsta4 | GST 5.7 | Mm | Dn | Decreased during differentiationhhh; no good d/t data; probably indirect. | 0009806360 | 0 |
| H19 | H19 | Hs | Up | No good d/t data; delayed induction; probably indirect. | 0009720909 | 0 |
| Ha1riii | Hoxa-1 Regulating | Mm | Up | Probably indirect (Hoxa-1). | 0010672899 | 0 |
| HBP17 | FGF-BP | Hs, Rn | Dn | No good d/t data; probably indirect. | 8702908; 10831072; 11077050 | 0 |
| HGF | hepatocyte growth factor | Hs | Dn | Rapid repression; specific ligands (in late-measurement studies); other NRs; probably indirect. | 0009886825; 11223164 | 0 |
| Hoxa5 | Hoxa5 | Mm | Up | Probably indirect. | 0010679930 | 0 |
| Htf 9c | Htf 9-c | Mm | – | In some cell types, RAR.RXR (as well as other RXR-containing complexes) bind to a DR1; no other evidence of RA regulation either way. | 0009417108 | 0 |
| IBSP | bone sialoprotein (BSP) | Hs | – | Motif; other NRs, but no direct evidence of RA involvement. | 0008061918; 0008702678; 10900268 | 0 |
| Ifng | IFN-γ | Mm, Hs | Dn | No good d/t data for RA alone; other NRs; probably indirect. | 1907993; 0008900159; 0009808170 | 0 |
| IGF2 | IGF-II, IGF-2 | Hs | vrs | Early induction, but the significance of the increase is not clear; mRNA decrease in some studies seems to be a late effect, probably indirect (possibly IGFBPs). | 0001375906; 0008364891; 0007527270; 0009258346; 0009688937 | 0 |
| IGFBP4 | IGFBP-4 | Hs, Ss | vrs | Generally studied during growth regulation; no good d/t data; other NRs; probably indirect (protein synthesis). | 0007686749; 0008640300; 0008536624; 0010601968 | 0 |
| Ihh | Ihh | Mm, Oc | Up | Rapid induction but probably indirect. | 9242425; 11281644 | 0 |
| Il12b | IL-12 p40 | Mm | Dn | Probably indirect (NFκB); specific ligands. | 10075655 | 0 |
| IL2 | IL-2 | Hs | vrs | No good d/t data; specific ligands in some inhibition studies; probably indirect. | 0001652063; 0007931079; 9130512 | 0 |
| IL8 | IL-8 | Hs, Mf | Up | Probably indirect. | 0007763262; 0010745031 | 0 |
| Itga8jjj | α-8 integrin | Rn | Up | Delayed induction during differentiation; probably indirect (protein synthesis). | 11181072 | 0 |
| Itgb5kkk | β 5 integrin | Gg | Dn | Indirect. | 0009893063 | 0 |
| Itgb7 | β 7 integrin | Mm | – | Motifs; no other evidence. | 0008318458 | 0 |
| IVL | involucrin | Hs | vrs | Differentiation associated; no good d/t; probably indirect (AP-1 in at least some systems). | 3858572; 2463259; 0001378029; 0008853895; 0008959344 | 0 |
| Kpna2lll | importin α | Rn | Up | No good d/t data; probably indirect (protein synthesis). | 11181072 | 0 |
| KRT1 | K1 | Hs | Dn | No good d/t data; there may be significant differences between in vitro and in vivo RA effects; AP-1 regulation; differentiation associated; probably indirect. | 2440897; 7522960; 0007516397; 0007510286 | 0 |
| KRT18 | K18, EndoB | Mm, Oc, Hs | Up | Induced during differentiation (or growth inhibition), rapidly in some cell types; some proliferation controls have been done; specific ligands; probably indirect (AP-1, Ets2); RA-sensitive Alu in Hs gene. | 1691021; 7514938; 0007526151; 0007667273; 8641545 | 0 |
| KRT19 | K19 | Hs | Up | Probably indirect (mRNA stability and AP-1 have been discussed); other NRs. | 6205395; 2414289; 0007505782; 0007506253; 8751982; 11026574 | 0 |
| KRT4 | K4 | Hs | vrs | No good d/t data; probably indirect. | 0008687453; 8751982; 8950195; 10692107 | 0 |
| KRT8 | K8, EndoA | Mm, Hs | Up | Induced during differentiation (or growth inhibition); induction rapid in some cell types; some proliferation controls; AP-1 regulation; specific ligands; probably indirect. | 1691021; 7505756; 8641545; 11010814 | 0 |
| Ldhb | LDH-B | Rn | Up | No good d/t data; during arrest or differentiation; probably indirect (protein synthesis). | 11181072 | 0 |
| lef1 | lef1 | Dr | Dn | Probably indirect. | 11002347 | 0 |
| Lmna | lamins A/C | Mm, Hs | vrs | Probably indirect. | 1282809; 1281113; 0009828104; 0010694499 | 0 |
| Lpl | LPL | Mm | – | No change in mRNA (but enzymatic activity decreased). | 0001610391 | 0 |
| Mbp | MBP | Rn | Up | Appears to be primarily a T3/TR system; may be activated by 9-cis/RXR in some cases. | 0009889331 | 0 |
| MMP1 | collagenase | Hs, Oc | Dn | Indirect; several mechanisms proposed. | 0002178224; 0001320254; 0007615643; 0008908199; 0009111003; 9537651; 0009888461 | 0 |
| MMP3 | Stromelysin | Rn, Hs, Bt, Ss | vrs | No good t/d data; possible differences between species in long term exposure; probably indirect. | 0002176152; 10548534; 10429942 | 0 |
| MMP9 | 92-kD gelatinase, MMP-9 | Hs | Dnmmm | Probably indirect. | 9565574; 9824620; 10646501; 11172606 | 0 |
| MPO | MPO | Hs | vrs | Differentiation associated; no good d/t data; a binding site in the Alu includes an allelic Sp1 site that may be important in APL; probably indirect. | 6321491; 0008662930; 0009326240 | 0 |
| MST1 | HGFL | Hs | Dn | No good d/t data; region responsible for RA inhibition identified; probably indirect. | 0009886825 | 0 |
| MUC4 | MUC4 | Hs | Up | No good d/t data; probably indirect (TGFb2 involved in some systems). | 10938282 | 0 |
| MYB | c-myb | Hs, Gc, Rn, Mm | vrs | Rapid induction by RA appears to be indirect; there is evidence of physical an RAR.MYB interaction (and mutual antagonism); inhibition appears to be indirect, but RXR-dependent. | 3380093; 0001323819; 8670250; 8598228; 0009576918; 0009714701; 0010614788 | 0 |
| NORPEG | NORPEG | Hs | Up | No good d/t data; probability of indirect mechanisms discussed. | 11042181 | 0 |
| Nppa | ANF, ANP | Rn, Hsnnn | Dn | No good d/t data; during growth or hypertrophy control; other NRs; responsive upstream region isolated; specific ligands; probably indirect. | 7611385; 0007638203; 8601621 | 0 |
| NPY1R | Y1R | Hs | Dn | Rapid decrease; at least partly due to decreased message stability; slowed by cyclohexamide; probably indirect. | 8978705; 9165460 | 0 |
| Nr2f1 | COUP-TF1 | Mm | Up | No good d/t data; delayed induction during differentiation in one study, but with some controls; probably indirect. | 0008314004; 0007947324; 0008804707; 9831119 | 0 |
| Nr2f 2 | ARP-1, COUP-TF II | Mm | Up | No good d/t data; delayed induction during differentiation in one study; some differentiation controls; probably indirect. | 0007947324; 0008804707 | 0 |
| NR4A1 | NGFI-B, Nur77 | Hs | Dn | The data from short-term work is hard to interpret but the level of repression is probably insignificant; longer-term work suggests an AP-1 intermediary. | 9070291; 10772826 | 0 |
| NRGN | RC3 | Rn | Up | Evidence of induction and receptor binding in early papers; no longer thought to be directly regulated by RA. | 0007898304; 0007730337; 0009282911 | 0 |
| Ntrk1ooo | TrkA | Rn, Gg, Hs | vrs | Upregulation in most papers; various differentiation controls have been used; mRNA stability may be involved; probably indirect. | 7988722; 0007496626; 7559588; 0008817533; 10784405 | 0 |
| OAS3ppp | 100-kD OAS | Hs | Up | No good d/t data; reporter induction; motif; probably indirect. | 0006435868; 2472992; 1677311; 11112351 | 0 |
| ODC1 | ODC | Hs | Dn | Probably indirect (protein synthesis), but the mRNA is very short-lived. | 2478272; 2295835 | 0 |
| OPRD1 | DOR | Hs, Rn | Up | No good d/t data; probably indirect. | 7932156; 8866697; 9219948 | 0 |
| Oprk1 | KOR | Mm | vrs | Indirect. | 11092879; 11222649 | 0 |
| OPRM1 | MOR | Hs | Up | No good d/t data; probably indirect. | 7932156; 9219948 | 0 |
| Otx2 | Otx2 | Mm, Xl, Gg | Dn | Promoter region conferring RA response identified, but no motif found; specific ligands (TTNPB repressed but TTNPB plus LG69 had no effect); physiological relevance of RA pathway questioned; expression normal in Aldh1a2 -/- embryos; probably indirect. | 7607086; 7748789; 7720578; 7669695; 9006080; 10192400 | 0 |
| PDGFA | PDGF-A | Hs, Mm | Dn | No good d/t data; down-regulated during differentiation; probably indirect. | 3215396; 2155144; 8274456 | 0 |
| Pdgfra | PDGF receptor α | Mm, Hs | Up | Region responsible for RA effect identified; no motif found; probably indirect (GATA-4 and Oct-4 have been discussed). | 2155144; 2174116; 7731723; 0008552100; 0008662786 | 0 |
| Pitx2 | Pitx2 | Mm | Up | Probably indirect. | 0010331971; 11245568 | 0 |
| Pk3 | PK | Mm | Dn | Isoform M2 decreased during differentiationqqq; no good d/t data; probably indirect. | 0009806360 | 0 |
| Plp | PLP | Rn | Up | Indirect. | 1374482; 7503983 | 0 |
| Ppara | PPAR-α | Mm | Up | No good d/t data; probably indirect. | 0010509805 | 0 |
| Pparg | PPAR-γ | Mm | Up | No good d/t data; probably indirect. | 0010509805 | 0 |
| Pthlh | PTHrP | Mm | Up | Probably indirect. | 9280059 | 0 |
| Ranbp1 | Htf 9-a/RanBP1 | Mm | – | RAR.RXR binding to a DR1 in some cell types; the site is required for maximal transcription; no other information about RA regulation. | 0009417108 | 0 |
| RB1 | Rb | Hs | Vrsrrr | No good d/t data; probably indirect. | 0001511698; 8502481; 7889981 | 0 |
| Rbbp7sss | pRbAp46 | Rn | Up | Dose and time unclear, but protein synthesis required; probably indirect. | 10667225 | 0 |
| Rex2 | Rex-2 | Mm | Dn | Suppressed late in differentiationttt; evidence from receptor knockouts; probably indirect. | 0009806360 | 0 |
| Rex3 | Rex-3 | Mm | Dn | Suppressed late in differentiationuuu; evidence from receptor knockouts; probably indirect. | 0009806360 | 0 |
| Rsdr1vvv | RDH, retSDR1 | Rn | Up | No good d/t data; probably indirect (protein synthesis). | 11181072 | 0 |
| Rxrg | RXR γ | Mm, Rn, Hs, Gg | Up | Many studies find no RA regulation; no good d/t data; other NRs; binding motif (prefers RXR.RXR); induction blocked by cyclohexamide; probably indirect. | 8269997; 8294402; 0009006910; 9075714 | 0 |
| Sarawww | Sar1a | Rn | Up | Dose and time unclear but protein synthesis is required; probably indirect. | 10667225 | 0 |
| Sat | SSAT | Ss, Bt, Rn | Up | No good d/t data; probably indirect (protein synthesis). | 9780334; 9831819; 11181072 | 0 |
| Serpinh1 | J6 serpin | Mm | Up | Promoter region responsible for RA effect identified; indirect (probably through GATA-4). | 0002981185; 0002842348; 0001639782; 7717974 | 0 |
| Shmt1xxx | shmt | Mm | Dn | Indirect; post-transcriptional. | 8863732 | 0 |
| SLA | SLAP | Hs | Up | Probably indirect. | 0009020066; 11179692 | 0 |
| SLC27A1 | FATP | Hs, Rn | Up | Probably indirect; specific ligands. | 0010777552 | 0 |
| Slc2a3 | GLUT 3 | Mm | Dnyyy | Decreased during differentiation; no good d/t data; probably indirect. | 0009806360 | 0 |
| SLC9A1 | Na+/H+ antiporter | Hs, Mm | Up | No good d/t data; induced during differentiation; probably indirect. | 1315322; 8388633; 7737975; 11168401 | 0 |
| Slc9a2 | NHE-2 | Rn | – | Motif; no other evidence. | 0009804979 | 0 |
| Sod1 | Cu/Zn superoxide dismutase | Ss, Hs, Mm | Dn | The decrease during differentiation is probably indirect (Hoxa-1); other studies have reported no change in SOD activity. | 2151307; 8389401; 10942599 | 0 |
| TERT | hTERT | Hs | Dn | No good d/t data; late suppression during differentiation; some differentiation controls; probably indirect. | 8709642; 10613358; 10786671 | 0 |
| THYb10zzz | Thymosin β 10 | Rn, Hs, Mm | Up | Probably indirect. | 1846397; 0002059565; 0001315216; 8925915 | 0 |
| TIMP1aaaa | Timp-1 | Hs | Up | No good d/t data; probably indirect (protein synthesis). | 0002824558; 1661164; 9664142; 10866818 | 0 |
| TNFRSF6 | CD95, Fas | Hs | Up | No good d/t data; some differentiation controls; specific retinoids; probably indirect. | 0009792441; 10733098; 11103825 | 0 |
| Tnfsf6 | FasL, CD95 ligand | Mm, Hs | Dn | No good d/t data for RA; specific ligands; other NRs; probably indirect (NUR77). | 0007565709; 0009792441; 11465095 | 0 |
| Trh | preprothyrotropin- releasing hormone | Mm | Dn | Indirect. | 0010537125 | 0 |
| Trp53 | p53 | Mm, Hs | vrs | Regulated during differentiation (or other phenotypic change); specific ligands; probably indirect, several mechanisms discussed. | 6287239; 2414665; 8484778; 7930673; 10327056; 11420666; 11526443 | 0 |
| Vcam1 | VCAM-1 | Mm, Hs, Rn | Up | No good d/t data; probably indirect (protein synthesis). | 7533155; 9022083; 11181072 | 0 |
| VEGF | VEGF/VPF | Rn, Hs, Cp | Dn | Rapid inhibition; specific ligands; AP-1 sites identified; probably indirect. | 8200985; 9804359; 0010617662; 10964585 | 0 |
| VIP | VIP | Hs | Up | Slow increase during differentiation but some controls have been done; increase is prior to morphological change; probably indirect. | 0001319016; 0007925107; 0009285932 | 0 |
| Zfp42 | Rex-1 | Mm | Dn | No good d/t data; differentiation associated; probably indirect. | 0002511439; 0008474450; 0009528758 | 0 |
c Called 17-β-HSD-II in PMID 0008013376.
d The Hs symbol and name is POU1F1: POU domain, class 1, transcription factor 1 (Pit1, growth hormone factor 1).
e It is not yet clear exactly what the active binding site(s) are. Orthologous control regions are definitely involved and there appears to be some degree of conservation in Mm and Rn.
f Rn promoter in Hs cells.
g See PMID 0010194513 for a brief review of RA and ApoA1.
h The sequence appears to come from chromosome 7 but may contain a large Line1 repeat.
i Figure 2B in PMID 0001700780 appears to show a data point which would satisfy our dose and time criteria. However, it is not discussed in the text.
j This is the Hs name. There is a 94% aa identity to rabbit OC2 according to OMIN.
k There has been some controversy about the metabolic products of the the gene(s) in different spp; also, Cyp26 may not be RA-inducible in some cells that nevertheless metabolize RA.
l It is not clear whether Stra7 and Gbx2 are different genes. The GB entries are virtually identical where they overlap. The Stra7 clone is effectively included in the Gbx-2 Ref Seq.
m The allelic variant GGTP1*C used in some studies is thought not to effect the generality of the RA work.
n Site from 2nd intron and flanking exon more or less conserved in Hs, Rn, Ma, Oc, Cf, Ss, Gg, and cats.
o Mm symbol and name.
p This assumes the Ggal gene RIHB (NCBI GI 434357) is orthologous to Mm Mdk.
q Interim Hs name; no Rn assignment.
r Rn data mentioned but not shown.
s The ability of RA to counteract estrogen through the OTX ERE is discussed in PMID 0001655807, and the ERE was used as a “negative RARE” in combination with transfected RARa, JUN, and ER.
t The figure demonstrating this is not easy to interpret.
u Rn promoter and exogenous RAR/RXR in Hs cells.
v Interim symbol and name.
w Earlier papers that do not distinguish enzyme forms are not considered here.
x Interim symbol and name.
y Interim symbol and name.
z Mm symbol and name.
aa Name by analogy to mammalian crystallins.
bb We assume DDX1 is the gene in question; there are other DEAD box proteins, of course, but the paper does not clearly distinguish them.
cc Interim symbol and name.
dd To us, the figure showing rapid induction is unconvincing; no dose is given, either.
ee It is not clear what has happened between times 0 and 24 hours in Figure 2b of PMID 0010674883.
ff It is not clear what has happened between times 0 and 24 hours in Figure 2b of PMID 0010674883.
gg F3 is frequently studied in APL cells because it is thought to be involved in the pathology of the disease. Some of the work cited here is in APL lines.
hh Interim symbol and name.
ii Probably Ins2 in Rn.
jj KRT6A seems to be the predominantly expressed K6 gene in Hs; the paper cited for Bt (in whom there are 3 K6 genes) is concerned with K6b; the motifs in PMID 0009326392 BLAST identically (and with the same single mismatch) to the provisional refseqs for both Hs K6 genes, KRT6A and KRT6b; the Hs AP-1 work is on K6b.
kk Most investigations so far have dealt with Erk activation, not message induction.
ll Interim symbol and name.
mm The gene studied now appears to be the ortholog of Msx2, not Msx1 (as thought at the time).
nn Mm symbol and name.
oo Interim symbol and name.
pp Induced in 3-dimensional systems but not in 2-dimensional cultures of keratinocytes and fibroblasts.
qq The effects of 9-cis, which are not covered here, have also been investigated. Cf. PMID 10403834 and PMID 0009717711 for example.
rr Interim Hs symbol and name.
ss SPRR1A, SPRR2, and SPRR3 are covered in some of these papers; the RA situation is basically the same.
tt Probable name, see PMID 11416019.
uu Hs DNA in Rn cells.
vv Suppression at 8 hours (100 nM) is discussed in PMID 10502285, but Figure 1B suggests it is significant by 4 h.
ww Both TOP2A and TOP2B have been studied, but most of the RA work has concentrated on 2A.
xx The statistical significance of a slight decrease at 6 h in PMID 11146166 is not clear.
yy An RARE half site seems to be marked in a GenBank entry but neither the site nor RA is mentioned in the associated paper.
zz No official name or symbol; no curated orthologs.
aaa Aggrecanase-1 is an alias for ADAMTS4; some of the papers listed here cover ADAMTS5 (aggrecanse-2) as well. MMP3 and MMP13 (q.v.) may also be involved.
bbb Probable Mm ortholog; no Rn assignment.
ccc High consentrations of retinoic acid inhibit BGLAP induction by vitamin D, but a well-characterized AP-1 response element is contained in the VDRE. Some experiments found neither induction nor suppression by RA alone.
ddd There is no evidence that RA has different effects on the expression of the splicing alternates, calcitonin and calcitonin gene related peptide (CGRP).
eee Several studies have also been done in Rn and Hs using 9-cis. No good d/t data there, either.
fff Rn sequences in HepG2 cells; no RA regulation seen in hamster.
ggg Interim symbol and name.
hhh An altered transcription rate could not be shown in nuclear run-on experiments (although controls worked as expected); this was attributed to the highly stable mRNA.
iii Symbol and name pending.
jjj Interim symbol and name.
kkk Mm symbol and name.
lll Interim symbol and name.
continued
Gene Table—Continued
mmm Very long exposure may induce expression in some systems.
nnn Promoter constructs from Hs used in Rn cells.
ooo Mm symbol and name.
ppp The older articles study enzyme activity without distinguishing OAS1, -2, and -3.
qqq An altered transcription rate could not be shown in nuclear run-on experiments (although controls worked as expected); this was attributed to the highly stable mRNA.
rrr Many studies have looked at mechanisms by which RA influences RB phosphorylation. They are not included here.
sss Interim symbol and name.
ttt An altered transcription rate could not be shown in nuclear run-on experiments (although controls worked as expected); this was attributed to the highly stable mRNA.
uuu An altered transcription rate could not be shown in nuclear run-on experiments (although controls worked as expected); this was attributed to the highly stable mRNA.
vvv Interim Mm symbol and name.
www Probable Mm ortholog; no Rn assignment.
xxx It is not clear whether the repressed gene was Shmt1 or Shmt2.
yyy An altered transcription rate could not be shown in nuclear run-on experiments (although controls worked as expected); this was attributed to the highly stable mRNA.
zzz Interim symbol and name.
aaaa Studies do not necessarily distinguish members of the TIMP family.
The species designations column
The third column of the Gene Table lists the “species” studied in the papers cited. Although we made no systematic attempt to classify animals below the genus level, most of the designations are accurate. The following abbreviations are used: Bt, Bos taurus (cattle); Cf, Canis familiaris (dogs); Cj, Coturnix japonica (quails); Cp, Cavia porcellus (guinea pigs); Dm, Drosophila melanogaster (fruit flies); Dr, Danio rerio (zebrafish); Gc, Geodia cydonium (Geodia sponges); Gg, Gallus gallus (chickens); Hs, Homo sapiens (people); Ma, Mesocricetus auratus (hamsters); Mf, Macaca fascicularis (macaques); Mm, Mus musculus (mice); Oc, Oryctolagus cuniculus (rabbits); Rn, Rattus norvegicus (rats); Ss, Sus scrofa (pigs); Tr, Takifugu rubripes; (puffer fish); Xl, Xenopus laevis (frogs).
The regulatory directions column
For each gene, we have noted the predominant regulatory direction attributed to RA, up or down. This can be problematic in situations where, intuitively, RA can effect opposite actions in different cellular contexts: up during differentiation, for example, and down during growth inhibition. Again, we concentrated on what was most frequently reported. Genes are marked ‘vrs’ (various) when there is no obvious predominant direction. For all such genes, it should be clear from our comments whether the category rating is based on a single regulatory direction or on the data taken as a whole. For example, there are several clear demonstrations that the rapid down-regulation of Myc is indirect in the cell types in which this has been investigated. This seems likely to apply whenever Myc is down-regulated. Its rapid up-regulation in other contexts, however, has not convincingly been shown to be indirect anywhere. Myc‘s Category 2 rating therefore refers to its rapid up-regulation following a moderate dose of RA in certain situations. The comments column should make this clear. Everything in the table is based on currently available data, of course, and as additional contexts are studied, more cell types, different developmental stages, unusual environmental situations, and so forth, the picture will only get more complex.
Stock phrases used in the summary column
Every phrase in the Gene Table and every category rating should be read with the implicit qualification, “in the cell types or at the developmental stages studied.” Even the paradigm of classical RA regulation, RARβ, is not under RA control at all times or in all cell types. To keep the table as concise as possible, and to make comparisons easier, we used the following stock phrases when applicable: 1) “No good d/t data” means we found no experiments using dose and time conditions within our limits for suggestive data. The phrase does not impugn the work referred to but was chosen for its brevity. In particular, minute-by-minute observations using physiological doses of ligand are only rarely relevant in clinical research or developmental work. In fact, pharmacological doses may be the only effective therapies in certain clinical situations and teratological doses have been indispensable in some truly seminal developmental studies. In ordinary circumstances, however, it is generally assumed that direct transcriptional modulation is rapid and that it can be initiated with a physiologically moderate dose of ligand. Ideally, unless there is a transport problem, one would like to see experiments using nanomolar concentrations of RA and making observations within minutes. However, the number of experiments conforming to these standards is very small, so we set 1 μM × 6 h as the upper limit for “suggestive” data. This was a necessary compromise given the range of scientific questions addressed in the papers consulted. 2) “Specific ligands” refers to either receptor-selective ligands or ligands that do not have the full complement of biological effects associated with all-trans retinoic acid (for example, ligands that help sort out AP-1 events). 3) The phrase “functional binding site” implies that a whole range of thoughtfully-designed tests has been performed, and that a more or less recognizable response element has been identified. The phrase is distinguished from such other notations as “functional motifs” (for which no dimer binding or native transcriptional verification has been made), “binding sites” (from which heterologous promoters can be driven), “motifs” (which are supported by sequence analysis only), and so forth. The phrase “no motif found” says that a promoter or other presumed control region was inspected in at least one of the papers cited, but that no candidate motif was found. 4) “Other NRs” indicates that other nuclear receptors are known to be involved in the gene's regulation in some cells. The importance of noting this stems from the cross-talk that can occur between nuclear receptors, and from the similarity of nuclear receptor binding sites (which can be confounding when extreme dose conditions are used). 5) “During differentiation” (or a similar phrase) indicates that the gene has only been studied during differentiation, growth control, proliferation control, cell cycle arrest, apoptosis, wound healing, hypertrophy, or any of the other wholesale cellular or phenotypic changes RA can effect. We did not always include such an annotation. 6) “ … not for RA … ” or “ … not for RA alone … ” means that the referenced experiments, or parts of them, have been done with ligands other than all-trans RA, usually 9-cis or a synthetic, or with RA plus an additional factor. 7) “d/t borderline” signals that while at least some data fall within our dose/time limits, they are right on the borderline. This is meant to draw attention to the compromise inherent in the limits imposed for “suggestive” data. 8) “Probably indirect” is more specific than it sounds. It indicates that a transcriptional intermediary, as opposed to another indirect mechanism, is most likely involved: RA regulates X and X regulates Y. The particular intermediary is noted in some cases.
The citations column
We have attempted to evaluate RA's role in the control of 532 genes and could not possibly cite every relevant paper. Each paper we do cite makes a point directly connected to the Gene Table: a first assertion of RA control, a regulatory direction, a time or dose curve, a binding site, a species, or something else. In addition, we have cited a (very) few papers of particular historical importance even though the research described may have preceded the experimental techniques or genetic models that underpin today's RA work. To save space, we have used PubMed Unique Identifiers (PMIDs) rather than traditional citations.
PMIDs are the unique record numbers assigned to journal articles at the National Library of Medicine. They can be used in PubMed, National Library of Medicine Gateway, and other National Institutes of Health databases to retrieve citations, abstracts, cross-links to GenBank sequences or other sequence-based information, external links to full-text articles where available, and so forth. Unmodified identifiers are valid queries, type or paste the number(s) into the Search Box, at all appropriate National Library of Medicine front ends, but in complex queries or in other databases the tag “[PMID]” may be required.
The category ratings column
The ratings reflect overall assessments. Experimental evidence varies from gene to gene and there is no algorithm that can assign a category automatically. Investigators use different techniques and have different scientific questions in mind; the quality of figures varies, and the threshold of “proof” varies from lab to lab. For each gene then, the rating expresses our overall reading of the evidentiary situation based on all the work considered. Again, not all of the studies were designed to investigate mechanisms, so we are imposing extrinsic considerations in some cases.
Category 0.
There is no particular reason to believe that this gene is directly regulated through the classical RA pathway.
Case 1
Indirect regulation has been demonstrated in a context that seems likely to apply generally and no other data suggest that direct regulation is likely in other contexts. Indirect regulation can include the existence of RA-regulated transcriptional intermediaries, non-transcriptional or post-transcriptional effects, and so forth.
Case 2
Hexamer motifs have been found in a location that might represent a regulatory unit, but no other evidence of RA involvement has been offered in any paper we know of.
Case 3
An historical correction has been made and the gene is no longer thought to be under RA control.
Category 1.
There is solid evidence that the gene is controlled by RA and no indirect mechanism has been demonstrated experimentally. At the same time, the available data do not justify a prediction, or even suggest which way a prediction should go: direct or indirect regulation.
Case 1
Induction or suppression has been shown, but the dose and/or time conditions exceed our limits for “suggestive” data.
Case 2
Physiological, clinical, or dietary information (or evidence from transgenics, knock-ins, or knockouts) strongly implicates RA, but there is no particular reason to posit direct regulation through the classical RA pathway.
Case 3
mRNA studies are lacking but protein studies or other evidence suggests that further work should be done.
Category 2.
The gene is a strong candidate for direct regulation, but specific data are lacking.
Case 1
Transcriptional effects have been demonstrated under suggestive dose and time conditions but i) no binding site connection has been made, or ii) the involvement of an RAR.RXR dimer is not clear.
Case 2
There is highly promising binding site information plus basic inductive or suppressive data.
Category 3.
A persuasive case has been made, or can be made based on currently available data, that the gene is directly regulated by RA in at least one genetically “normal” cell type.
Requirement 1
Transcription-based induction or suppression (within the limits of 1 μM or less × 6 h or less) has been confirmed in some reasonably general context.
Requirement 2
Evidence of RAR.RXR involvement has been produced or strongly implied.
Requirement 3
A functional binding site, preferably conserved, has been found and tested in a broad panel of experiments.
RESULTS AND DISCUSSION
The number of genes per category
We have evaluated published data pertaining to RA's regulation of 532 genes and have summarized the data in the Gene Table. Based on current research, 27 of these genes are unquestionably controlled through the classical RA pathway in some cellular context(s). Genes falling into this category were subjected to a high level of scrutiny in order to ensure, as far as possible, that they would never have to be removed, although indirect mechanisms may be used in other contexts as well. They are marked as Category 3 genes. Another 105 genes are in Category 2. They can be modulated at the transcriptional level in less than 6 h following an administration of 1 μM RA or less, but other indicators of direct regulation have not yet been explored. In most cases, the data still lacking relate to response elements or RAR.RXR involvement.
Category 0 encompasses two cases. First, there are 124 genes that seem to be regulated indirectly in the contexts studied. We are aware of no data or arguments suggesting that these genes might be directly regulated through the classical RA pathway in other cellular contexts. Nine other genes (Adh1, BTK, FSCN2, Htf9c, IBSP, Itgb7, Lpl, Ranbp1, and Slc9a2) were also put into Category 0. They are discussed in the literature, but there is no strong reason to believe that they are regulated by RA at the transcriptional level. In two cases, Adh1 and Lpl, suspected or predicted mRNA changes were not confirmed, and while most of the others contain motifs resembling RA response elements, there is no evidence suggesting that these motifs, which can be highly ambiguous in the best of circumstances, represent biologically active retinoic acid response elements.
The remaining 267 genes, slightly more than half of those we evaluated, fall into Category 1. They are regulated by RA in some way, but the data available at present do not allow us to predict direct versus indirect control. Most have not yet been studied except in long-term or high-dose contexts, and for many, the ultimate interest has been clinical, developmental, or diagnostic rather than mechanistic. Additional work will need to be done to push these genes into more informative categories.
In fact, future research may change the classification status of any gene in the table. The method used to select Category 3 genes was designed to be sufficiently rigorous that no gene would easily be struck from the group, but there is no reason why any one of them might not be regulated indirectly in other contexts as well. Beyond that, we expect future research to find that many of the Category 2 genes are direct targets, and that some of the Category 1 genes are as well. In fact, some of the Category 0 genes may turn out to be direct targets too, but in contexts that have not yet been studied.
Regulatory direction
In terms of regulatory direction, 311 genes are always or almost always up-regulated in the contexts studied, 109 are always or almost always down-regulated, and the rest are quite variable. Most investigators now believe that direct regulation through the classical RA pathway is always inductive, although there is no theoretical reason why this should be so (and it is not true of some other transcription factors). Nevertheless, all the Category 3 genes are up-regulated and only three of the Category 2 genes are usually down-regulated. One Category 3 gene, Hoxb1, is marked “various” because it can be directly up-regulated in some contexts, but down-regulated, probably indirectly, in others. Given that many transcriptional events seem to be regulated cyclically, a “various” regulatory direction should probably be much more common than the data imply; most likely this is due to a lack of measurements taken along a fine enough time continuum. Table 2 summarizes category and direction data for the 532 genes. (The reader is reminded that gene expression in the presence of RA is the topic here. The repression of basal transcription by RAR.RXR in the absence of RA is an entirely different matter.)
TABLE 2Category and direction summary
| Category/Regulatory Direction | 0 | 1 | 2 | 3 | Total |
|---|---|---|---|---|---|
| Up | 63 | 130 | 92 | 26 | 311 |
| Down | 40 | 66 | 3 | 109 | |
| Variable | 21 | 71 | 10 | 1 | 103 |
| NA | 9 | 9 | |||
| Total | 133 | 267 | 105 | 27 | 532 |
Genes regulated by retinoic acid, predominant regulatory direction versus gene ratings (see text). NA, direction not determined in the literature or no mRNA regulation found.
The types of genes regulated
Not surprisingly, the set of genes currently known to be regulated directly through the classical RA pathway does not form a unified or predictable group, either in function or in sequence. (For the record, the human versions of these 27 genes are spread over 13 autosomal chromosomes.) However, two subsets deserve special mention: i) genes that are somehow related to the handling, metabolism, function, or presumed evolutionary history of the retinoids, and ii) genes containing homeobox domains. Using symbols from the Gene Table, the first group includes RARA, RARB, RARG, Rbp1, and CRABP2, together with several more tenuous members: ADH1C (which can metabolize retinol), CRYAB (which is loosely related to photoreception), and Drd2 (which contains a rhodopsin family, 7 transmembrane receptor domain). The other subset, genes that contain homeobox domains, consists of Hoxa1, HOXA4, Hoxb1, Hoxb4, Hoxd4, Cdx1, and Pit1.
Although no regulatory or evolutionary theory formally justifies it so far, it is tempting to see a certain logic in several other genes directly regulated by RA: HSD17B1 is involved in the function of other nuclear receptors; H1F0 is activated at differentiation and points of development; one of SFTPB's functions is developmental; IL2RA is involved in apoptosis; Ucp1 is expressed only in brown adipose tissue (and is therefore connected to dietary lipids); ETS1 ultimately derives from the E26 virus (and a number of viral control regions contain sequences that can respond to RA); Foxa1 and Egr1 are expressed early in differentiation. The other Category 3 genes are CD38 (which was originally identified as a differentiation antigen), Tgm2, and Pck1.
We found 105 Category 2 genes that can be more or less rapidly up- or down-regulated at the transcriptional level in the presence of RA. Some of these genes are probably regulated directly. It would be surprising if there were a common thread among them, and there is not. They encode proteins of almost every imaginable type.
However, several domain architectures turn up a number of times among the Category 2 and 3 genes and should probably be mentioned. Taking the 132 genes in these two categories together, 11 contain homeobox domains (Cdx1, GBX2, Hoxa1, HOXA4, Hoxb1, Hoxb4, Hoxd4, LHX1, Meis1, NCX, and Pit1) and six encode zinc finger proteins (NR2C2, NR4A3, RARA, RARB, RARG, and Egr1). Of those six, five are nuclear receptors with both c4 zinc finger domains and nuclear receptor ligand-binding domains. Five of the genes in the two categories are from the lipocalin/cytosolic fatty-acid binding protein family (APOD, Crabp1, CRABP2, Rbp1, and RBP4); and five contain tyrosine kinase catalytic, or eukaryotic protein kinase, domains (CSF1R, EGFR, LYN, Tgfbr1, and Tgfbr2). Three of the genes encode helix-loop-helix DNA-binding domain sequences (MYC, MYCN, and Srebf1); three encode short chain dehydrogenases (HSD17B1, HSD17B2, and RDHL); and three contain TGF-β propeptide domains (Ebaf, Gdf5, and Tgfb3).
State of the science
Intuitively, the number of Category 3 genes found in this work is surprisingly small, given the conservation of three RAR genes plus a triad of RXRs and multiple isoforms of all. The largest cohesive group of Category 2 or 3 genes consists of those somehow connected to the retinoids or nuclear receptors, the “infrastructure” of the regulatory system itself. And while evolution may not be particularly parsimonious, one suspects that the machinery of the classical RA pathway with all its complexities and autoregulatory loops has been conserved, not to regulate itself, but because it is uniquely useful in controlling, directly or indirectly, a particular range of genetic events in various cells and at different times of life. This suggests that the group of Category 3 genes will grow as new data become available on genes already in the table, and as new targets are discovered. There is circumstantial evidence for this, too. Since at least the mid-1980s, subtraction or differential-display experiments using RA have been turning up “novel” genes and there is no sign that this is slowing down. Many of these genes have not been investigated beyond the original paper mentioning them, and most are probably cases of indirect regulation. Nevertheless, this adds an exciting dimension to the RA field and points to quite a few experiments waiting to be done.
In works that deal with a large number of genes, it has become customary to summarize functions, family memberships, and other quiddities, “ontologies” as they are now called in a puzzling use of the word. This is done as a first step in finding underlying biological regularities, and we have done it for that reason in this paper. However, its significance should not be overplayed. Duplications of whole genes, coding plus regulatory and non-coding regions, do not endure evolutionary time unchanged, and it is by now perfectly clear that non-coding regions are far more labile than coding regions. While some progress has been made in identifying regulatory elements analytically, see (
26
) or (27
), for example, intervening sequences seem to be highly variable. Indeed, the evolutionary comings and goings of regulatory signals remain almost completely mysterious, and RA response elements, which are almost always found in traditional promoters or extended, multi-function enhancers, are short, degenerate, ambiguous signals ripe for evolutionary experimentation. One would therefore expect only coincidental functional or formal resemblances among the complete set of genes controlled by RA. What this tells us is that many interesting and surprising results remain to be found: genes whose regulation by retinoic acid is not a priori predictable.Over the last quarter century, a substantial body of knowledge has been built up concerning gene expression regulation by RA. That work has contributed significantly to our understanding of context-regulated transcription, vertebrate development, and a host of important clinical issues. From the particular perspective of this paper, much of the work we consulted was tantalizingly close to helping answer the direct-versus-indirect question even though it was not originally designed to address that question at all. In other cases, elucidating a molecular pathway was a primary research goal and a clear answer was determined; and in a few cases, intriguing scientific issues have turned up when regulatory mechanisms do not seem to be as clear-cut as originally expected, as with LAMB1 (
28
, 29
, 30
, 31
, 32
). Of course, many RA studies seek clinical or nutritional information, and the poignant need for such studies is beyond question; yet in the larger scheme, knowing which regulatory events are direct and which are indirect can perhaps lead to superior pharmacological and nutritional protocols as well as to progress in basic science.Endnote
For many of the genes considered in this paper, there are entire labs with years of expertise and a broader interest than the gene's potential regulation by RA. People from these labs may see connections or alternatives that were not obvious to us. Similarly, the number of papers potentially relevant to a work of this sort is huge, and we were repeatedly reminded that neither titles nor abstracts need hint at all the results reported. Finally, while MeSH indexing and MEDLINE coding are invaluable tools and basic to virtually every biomedical research project now carried out, they are just as fallible as bench work. For all of these reasons, it would be surprising if we had not missed important ideas or papers.
We think of this paper as a working document and hope that our errors and oversights will generously be pointed out by our colleagues so that the table can be updated, improved, and maintained, by us or by another group, as an evolving assessment of RA's genetic workings.
Acknowledgments
This work was supported by the Norwegian Cancer Society, the Research Council of Norway, and the Throne Holst Foundation.
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Article info
Publication history
Published online: November 01, 2002
Accepted:
June 17,
2002
Received:
November 2,
2001
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© 2002 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.
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