出版社:American Society for Biochemistry and Molecular Biology
摘要:Lipid synthesis is required for cell growth and is subject topharmacologic regulation. Keratinocyte growth factor (KGF) stimulatesproliferation and lipogenesis in H292 cells, a pulmonary epithelialcancer cell line, but the signaling pathways are not known.KGF stimulated the expression of the transcription factors sterol-regulatoryelement binding protein-1 (SREBP-1), CCAAT/enhancer bindingprotein (C/EBP), and C/EBP and two key enzymes involved inlipogenesis, 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 ofSREBP-1, SCD-1, and FAS by KGF was inhibited by the JNK inhibitorSP600125 and the phosphatidylinositol 3-kinase (PI3K) inhibitorLY294002 but not by the ERK inhibitor PD98059. Using FAS andSCD-1-luciferase promoter constructs, we observed that KGF stimulatedthe transcription of these promoters and that exogenous cholesterolinhibited the induction. Mutation of the SREBP-1 binding sitein the SCD-1 promoter abolished the effect of KGF on SCD-1 transcription.In addition, overexpression of active SREBP-1 directly stimulatedSCD-1 and FAS. Conversely, adenovirus-mediated overexpressionof a dominant negative form of SREBP-1 inhibited the KGF effecton FAS and SCD-1 expression.
In summary, we conclude that KGF requires both PI3K and JNKsignaling pathways to induce SREBP-1, which in turn inducesSCD-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