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.

Hypoxia‐induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis

“…Finally, MS revealed that hypoxia altered the ubiquitination of Four and a half LIM domain 1 (Fhl1). Fhl1 is involved in muscle development 57 and plays an important role in gene transcription and cell proliferation, differentiation, apoptosis and cytoskeletal remodeling 58 . There is previous evidence that Fhl1 is important in vascular remodeling in PH, 57 though we were unable to find any reports of Fhl1 ubiquitination.…”

“…Fhl1 is involved in muscle development 57 and plays an important role in gene transcription and cell proliferation, differentiation, apoptosis and cytoskeletal remodeling. 58 There is previous evidence that Fhl1 is important in vascular remodeling in PH, 57 though we were unable to find any reports of Fhl1 ubiquitination. We observed increased ubiquitination of Fhl1 at K295 (3.1 FC H/N) and decreased ubiquitination at K173 (2.1 FC N/H).…”

Smad4 Inhibits VEGF‐A and VEGF‐C Expressions via Enhancing Smad3 Phosphorylation in Colon Cancer

“…Studies have shown that many growth factors and their receptors play roles in tumor invasion and metastasis (Bachelder et al, ), including the VEGF system, and the regulation of this signaling axis has become a major focus of current research. A previous study (Zhou et al, ) showed that a reduction in Smad4 abrogated FHL1‐mediated inhibition of the VEGF promoter activity in HepG2 cells. Overexpression of FHL1 and Smad4 synergistically inhibited the secretion of VEGF, and knockdown of Smad4 and FHL1 had opposite effects.…”

Blood Leukocyte Transcriptional Modules and Differentially Expressed Genes Associated with Disease Severity and Age in COVID-19 Patients

“…The Hhub FHL1 encodes a four-and-a-half-LIM-domain protein involved in gene transcription regulation, cytoarchitecture, cell proliferation, and signal transduction [68]. Interestingly, FHL1 inhibits the vascular endothelial growth factor (VEGF) expression [69] and elevated serum levels of VEGF were positively correlated with disease severity in COVID-19 [70]. The Hhub MISP3 codes for a protein involved in spindle orientation and mitotic progression [71].…”