Egr-1 and serum response factor are involved in growth factors- and serum-mediated induction of E2-EPF UCP expression that regulates the VHL-HIF pathway
✍ Scribed by Jung Hwa Lim; Cho-Rok Jung; Chan-Hee Lee; Dong-Soo Im
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 413 KB
- Volume
- 105
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
Abstract
E2‐EPF ubiquitin carrier protein (UCP) has been shown to be highly expressed in common human cancers and target von Hippel‐Lindau (VHL) for proteosomal degradation in cells, thereby stabilizing hypoxia‐inducible factor (HIF)‐1α. Here, we investigated cellular factors that regulate the expression of UCP gene. Promoter deletion assay identified binding sites for early growth response‐1 (Egr‐1) and serum response factor (SRF) in the UCP promoter. Hepatocyte or epidermal growth factor (EGF), or phorbol 12‐myristate 13‐acetate induced UCP expression following early induction of Egr‐1 expression in HeLa cells. Serum increased mRNA and protein levels of SRF and UCP in the cell. By electrophoretic mobility shift and chromatin immunoprecipitation assays, sequence‐specific DNA‐binding of Egr‐1 and SRF to the UCP promoter was detected in nuclear extracts from HeLa cells treated with EGF and serum, respectively. Overexpression of Egr‐1 or SRF increased UCP expression. RNA interference‐mediated depletion of endogenous Egr‐1 or SRF impaired EGF‐ or serum‐mediated induction of UCP expression, which was required for cancer cell proliferation. Systemic delivery of EGF into mice also increased UCP expression following early induction of Egr‐1 expression in mouse liver. The induced UCP expression by the growth factors or serum increased HIF‐1α protein level under non‐hypoxic conditions, suggesting that the Egr‐1/SRF‐UCP‐VHL pathway is in part responsible for the increased HIF‐1α protein level in vitro and in vivo. Thus, growth factors and serum induce expression of Egr‐1 and SRF, respectively, which in turn induces UCP expression that positively regulates cancer cell growth. J. Cell. Biochem. 105: 1117–1127, 2008. © 2008 Wiley‐Liss, Inc.