title: FHL1 and Smad4 synergistically inhibit vascular endothelial growth factor             expression.
abstract: Vascular endothelial growth factor (VEGF) plays an important role in many disease states, including ischemia, chronic and acute inflammation, and pathologies associated with angiogenesis such as tumors and wounds. A number of factors regulate VEGF promoter activity and VEGF expression such as four and a half LIM domains 1 (FHL1) and Smad4. FHL1 belongs to a family of LIM-only proteins that regulate gene transcription, cell proliferation, differentiation and apoptosis. Smad4 is a tumor suppressor gene, initially identified as deleted in pancreatic carcinoma locus 4 (DPC4). The aim of this study was to determine whether FHL1 and Smad4 inhibited VEGF signaling. HepG2 cells were transfected with the VEGF-Luc reporter, Smad4 and FHL1 or Smad4 and FHL1 siRNA. Results showed that the overexpression of FHL1 and Smad4 synergistically inhibited the promoter activity, mRNA expression and secretion of VEGF, whereas knockdown of endogenous Smad4 and FHL1 had opposite effects. Moreover, the reduction of endogenous Smad4 eliminated FHL1-mediated inhibition of the VEGF promoter activity. In conclusion, a cooperative regulation of VEGF signaling by FHL1 and Smad4 was evidenced, which may provide a novel regulation mechanism underlying cancer development and progression.
authors.affiliation: Medical School, Nankai University, Tianjin 300071, P.R. China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhou
authors.forename: Juming
authors.initials: J
authors.lastname: Lu
authors.forename: Jingtao
authors.initials: J
authors.lastname: Dou
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Lv
authors.forename: Xi
authors.initials: X
authors.lastname: Qin
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
mesh_terms: D015870:Gene Expression; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: C101149:FHL1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D034741:RNA, Small Interfering; D051901:Smad4 Protein; D042461:Vascular Endothelial Growth Factor A