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* Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206
Department of Biochemistry and Molecular Biology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614
Published, JLR Papers in Press, September 14, 2005. DOI 10.1194/jlr.M500154-JLR200
1 To whom correspondence should be addressed. e-mail: masonb{at}njc.org
Lipid synthesis is required for cell growth and is subject to pharmacologic regulation. Keratinocyte growth factor (KGF) stimulates proliferation and lipogenesis in H292 cells, a pulmonary epithelial cancer cell line, but the signaling pathways are not known. KGF stimulated the expression of the transcription factors sterol-regulatory element binding protein-1 (SREBP-1), CCAAT/enhancer binding protein 
(C/EBP), and C/EBP
and two key enzymes involved in lipogenesis, FAS and stearoyl coenzyme A desaturase-1 (SCD-1). We found that KGF induced rapid activation of Akt, p70 S6K, JNK, and extracellular signal-regulated (ERK). Induction of SREBP-1, SCD-1, and FAS by KGF was inhibited by the JNK inhibitor SP600125 and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 but not by the ERK inhibitor PD98059. Using FAS and SCD-1-luciferase promoter constructs, we observed that KGF stimulated the transcription of these promoters and that exogenous cholesterol inhibited the induction. Mutation of the SREBP-1 binding site in the SCD-1 promoter abolished the effect of KGF on SCD-1 transcription. In addition, overexpression of active SREBP-1 directly stimulated SCD-1 and FAS. Conversely, adenovirus-mediated overexpression of a dominant negative form of SREBP-1 inhibited the KGF effect on FAS and SCD-1 expression.
In summary, we conclude that KGF requires both PI3K and JNK signaling pathways to induce SREBP-1, which in turn induces SCD-1 and FAS expression in H292 cells.
Abbreviations: Akt, Akt/protein kinase B; C/EBP, CCAAT/enhancer binding protein; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; KGF, keratinocyte growth factor; KGFR, keratinocyte growth factor receptor; MAPK, mitogen-activated protein kinase; PDGF, platelet-derived growth factor; PFU, plaque forming units; PI, phosphatidylinositol; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PPAR
, peroxisome proliferator-activated receptor ; SCAP, sterol-regulatory element binding protein cleavage-activating protein; SCD-1, stearoyl coenzyme A desaturase-1; SREBP, sterol-regulatory element binding protein
Supplementary key words H292 cells • lipogenesis • lung cancer • keratinocyte growth factor • phosphatidylinositol 3-kinase • sterol-regulatory element binding protein-1
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