Redox-Regulated Recruitment of the Transcriptional Coactivators CREB-Binding Protein and SRC-1 to Hypoxia-Inducible Factor 1α

Author:

Carrero Pilar1,Okamoto Kensaku12,Coumailleau Pascal1,O'Brien Sallyann1,Tanaka Hirotoshi3,Poellinger Lorenz1

Affiliation:

1. Department of Cell and Molecular Biology, Karolinska Institutet, S-171 77 Stockholm, Sweden, 1 and

2. Second Department of Internal Medicine, Asahikawa Medical College, Asahikawa 078-8510, 2 and

3. Department of Clinical Immunology and AIDS Research Center Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, 3 Japan

Abstract

ABSTRACT Hypoxia-inducible factor 1α (HIF-1α) 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-1α and enhance its transactivation potential in a hypoxia-dependent manner. HIF-1α 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-1α function in hypoxic cells. Given the absence of cysteine residues in one of the Ref-1-regulated transactivation domains of HIF-1α, 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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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