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.

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)-1alpha. 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-1alpha protein level under non-hypoxic conditions, suggesting that the Egr-1/SRF-UCP-VHL pathway is in part responsible for the increased HIF-1alpha 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.

• Authors: Jung Hwa Lim, Cho-Rok Jung, Chan-Hee Lee, Dong-Soo Im
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 105 Issue 4 Pg. 1117-27 (Nov 01 2008) ISSN: 1097-4644 [Electronic] United States
• PMID: 18780286 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• EGR1 protein, human
• Early Growth Response Protein 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Intercellular Signaling Peptides and Proteins
• Serum Response Factor
• Ube2S protein, human
• Ubiquitin-Conjugating Enzymes
• Von Hippel-Lindau Tumor Suppressor Protein

Topics

• Cell Proliferation
• Early Growth Response Protein 1 (physiology)
• HeLa Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Intercellular Signaling Peptides and Proteins (pharmacology)
• Neoplasms (pathology)
• Protein Stability
• Serum
• Serum Response Factor (physiology)
• Transcriptional Activation (drug effects)
• Ubiquitin-Conjugating Enzymes (genetics)
• Von Hippel-Lindau Tumor Suppressor Protein (metabolism)