Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha.

Abstract

Hypoxia-inducible factor 1alpha (HIF-1alpha) functions as a transcription factor that is activated by decreased cellular oxygen concentrations to induce expression of a network of genes involved in angiogenesis, erythropoiesis, and glucose homeostasis. Here we demonstrate that two members of the SRC-1/p160 family of transcriptional coactivators harboring histone acetyltransferase activity, SRC-1 and transcription intermediary factor 2 (TIF2), are able to interact with HIF-1alpha and enhance its transactivation potential in a hypoxia-dependent manner. HIF-1alpha contains within its C terminus two transactivation domains. The hypoxia-inducible activity of both these domains was enhanced by either SRC-1 or the CREB-binding protein (CBP)/p300 coactivator. Moreover, at limiting concentrations, SRC-1 produced this effect in synergy with CBP. Interestingly, this effect was strongly potentiated by the redox regulatory protein Ref-1, a dual-function protein harboring DNA repair endonuclease and cysteine reducing activities. These data indicate that all three proteins, CBP, SRC-1, and Ref-1, are important components of the hypoxia signaling pathway and have a common function in regulation of HIF-1alpha function in hypoxic cells. Given the absence of cysteine residues in one of the Ref-1-regulated transactivation domains of HIF-1alpha, it is thus possible that Ref-1 functions in hypoxic cells by targeting critical steps in the recruitment of the CBP-SRC-1 coactivator complex.

• Authors: P Carrero, K Okamoto, P Coumailleau, S O'Brien, H Tanaka, L Poellinger
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 20 Issue 1 Pg. 402-15 (Jan 2000) ISSN: 0270-7306 [Print] United States
• PMID: 10594042 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nuclear Proteins
• Trans-Activators
• Transcription Factors
• CREB-Binding Protein
• Histone Acetyltransferases
• Nuclear Receptor Coactivator 1
• Oxygen

Topics

• Animals
• COS Cells
• CREB-Binding Protein
• Cell Hypoxia (genetics)
• DNA-Binding Proteins (genetics, metabolism)
• Histone Acetyltransferases
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nuclear Proteins (genetics, metabolism)
• Nuclear Receptor Coactivator 1
• Oxidation-Reduction
• Oxygen (metabolism)
• Trans-Activators (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Transcriptional Activation