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Title: Complex regulation of the transactivation function of hypoxia-inducible factor-1αby direct interaction with two distinct domains of the creb-binding protein/p300
Authors: Ruas, J.L.
Berchner-Pfannschmidt, U.
Malik, S.
Gradin, K.
Fandrey, J.
Roeder, R.G.
Pereira, T.
Poellinger, L. 
Issue Date: 22-Jan-2010
Citation: Ruas, J.L., Berchner-Pfannschmidt, U., Malik, S., Gradin, K., Fandrey, J., Roeder, R.G., Pereira, T., Poellinger, L. (2010-01-22). Complex regulation of the transactivation function of hypoxia-inducible factor-1αby direct interaction with two distinct domains of the creb-binding protein/p300. Journal of Biological Chemistry 285 (4) : 2601-2609. ScholarBank@NUS Repository.
Abstract: Activation of transcription in response to low oxygen tension is mediated by the hypoxia-inducible factor-1 (HIF-1). HIF-1 is a heterodimer of two proteins: aryl hydrocarbon receptor nuclear translocator and the oxygen-regulated HIF-1α. The C-terminal activation domain of HIF-1α has been shown to interact with cysteine/histidine-rich region 1 (CH1) of the coactivator CBP/p300 in a hypoxia-dependent manner. However, HIF forms lacking C-terminal activation domain (naturally occurring or genetically engineered) are still able to activate transcription of target genes in hypoxia. Here, we demonstrate that the N-terminal activation domain (N-TAD) of HIF-1α interacts with endogenous CBP and that this interaction facilitates its transactivation function. Our results show that interaction of HIF-1α N-TAD with CBP/p300 is mediated by the CH3 region of CBP known to interact with,among other factors, p53. Using fluorescence resonance energy transfer experiments, we demonstrate that N-TAD interacts with CH3 in vivo. Coimmunoprecipitation assays using endogenous proteins showed that immunoprecipitation of CBP in hypoxia results in the recovery of a larger fraction of HIF-1α than of p53. Chromatin immunoprecipitation demonstrated that at 1%O2 CBP is recruited to a HIF-1α but not to a p53 target gene. Upon activation of both pathways, lower levels of chromatin-associated CBP were detected at either target gene promoter. These results identify CBP as the coactivator directly interacting with HIF-1α N-TAD and mediating the transactivation function of this domain. Thus, we suggest that in hypoxia HIF-1α is a major CBP-interacting transcription factor that may compete with other CBP-dependent factors, including p53, for limiting amounts of this coactivator, underscoring the complexity in the regulation of gene expression by HIF-1α. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
Source Title: Journal of Biological Chemistry
ISSN: 00219258
DOI: 10.1074/jbc.M109.021824
Appears in Collections:Staff Publications

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