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Papers In Press, published online ahead of print May 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800375-JLR200

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Journal of Lipid Research, Vol. 50, 820-831, May 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements

Hai Li, Wei Chen, Yue Zhou, Parveen Abidi, Orr Sharpe, William H. Robinson, Fredric B. Kraemer and Jingwen Liu¹

Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of a six figures and one table.

This study was supported by the Department of Veterans Affairs (Office of Research and Development, Medical Research Service) and by grants (1RO1 AT002543-01A1 and 1R21 AT003195-01A2) from the National Center for Complementary and Alternative Medicine.

Published, JLR Papers in Press, January 13, 2009.

¹ To whom correspondence should be addressed. e-mail: jingwen.liu{at}med.va.gov

The 3'untranslated region (UTR) of human LDL receptor (LDLR) mRNA contains three AU-rich elements (AREs) responsible for rapid mRNA turnover and mediates the stabilization induced by berberine (BBR). However, the identities of the specific RNA binding proteins involved in the regulation of LDLR mRNA stability at the steady state level or upon BBR treatment are unknown. By conducting small interfering RNA library screenings, biotinylated RNA pull-down, mass spectrometry analysis, and functional assays, we now identify heterogeneous nuclear ribonucleoprotein D (hnRNP D), hnRNP I, and KH-type splicing regulatory protein (KSRP) as key modulators of LDLR mRNA stability in liver cells. We show that hnRNP D, I, and KSRP interact with AREs of the LDLR 3'UTR with sequence specificity. Silencing the expression of these proteins increased LDLR mRNA and protein levels. We further demonstrate that BBR-induced mRNA stabilization involves hnRNP I and KSRP, as their cellular depletions abolished the BBR effect and BBR treatment reduced the binding of hnRNP I and KSRP to the LDLR mRNA 3'UTR. These new findings demonstrate that LDLR mRNA stability is controlled by a group of ARE binding proteins, including hnRNP D, hnRNP I, and KSRP. Our results suggest that interference with the ability of destabilizing ARE binding proteins to interact with LDLR-ARE motifs is likely a mechanism for regulating LDLR expression by compounds such as BBR and perhaps others.

Supplementary key words 3'untranslated region • berberine • mRNA stability • hypercholesterolemia

Abbreviations: ARE, AU-rich element; ARE-BP, ARE binding protein; BBR, berberine; CDS, coding sequence; CPSF1, cleavage and polyadenylation specific factor; ELAVL1, embryonic lethal abnormal vision Drosophila-like 1; HMGCR, HMG-CoA reductase; hnRNP, heterogeneous nuclear ribonucleoprotein; IMP3, IGF-II mRNA binding protein 3; KSRP, KH-type splicing regulatory protein; LDLR, LDL receptor; MS, mass spectrometry; RBP, RNA binding protein; siRNA, small interfering RNA; UTR, untranslated region; wt, wild type

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