title: KGF induces lipogenic genes through a PI3K and JNK/SREBP-1 pathway in H292 cells.
abstract: 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 alpha (C/EBPalpha), and C/EBPdelta 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.
authors.affiliation: Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chang
authors.forename: Jieru
authors.initials: J
authors.lastname: Wang
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Lu
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Thewke
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mason
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000494:pharmacology; D053222:Fas Ligand Protein; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008055:Lipids / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008055:Lipids; D008562:Membrane Glycoproteins; D051780:Sterol Regulatory Element Binding Protein 1; D048069:Tumor Necrosis Factors; D051523:Fibroblast Growth Factor 7; D002784:Cholesterol; D013230:Stearoyl-CoA Desaturase; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases