Article
- The EMBO Journal (2005) 24, 3846 - 3858
- doi:10.1038/sj.emboj.7600846
Published online: 20 October 2005
Subject Categories:
Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression
Lawryn H Kasper1,a, Fayçal Boussouar1,a, Kelli Boyd2, Wu Xu1, Michelle Biesen1, Jerold Rehg2, Troy A Baudino1,b, John L Cleveland1 and Paul K Brindle1
- Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN, USA
- Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA
Correspondence to:
Paul K Brindle, Department of Biochemistry, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105, USA. Tel.: +1 901 495 2522; Fax: +1 901 525 8025; E-mail: paul.brindle@stjude.org
aThese authors contributed equally to this study
bPresent address: Department of Cell and Developmental Biology, University of South Carolina, Columbia, SC 29209, USA
Received 26 July 2005; Accepted 28 September 2005
Abstract
The C-terminal activation domain (C-TAD) of the hypoxia-inducible transcription factors HIF-1
and HIF-2 binds the CH1 domains of the related transcriptional coactivators CREB-binding protein (CBP) and p300, an oxygen-regulated interaction thought to be highly essential for hypoxia-responsive transcription. The role of the CH1 domain in vivo is unknown, however. We created mutant mice bearing deletions in the CH1 domains (
CH1) of CBP and p300 that abrogate their interactions with the C-TAD, revealing that the CH1 domains of CBP and p300 are genetically non-redundant and indispensable for C-TAD transactivation function. Surprisingly, the CH1 domain was only required for an average of 
35–50% of global HIF-1-responsive gene expression, whereas another HIF transactivation mechanism that is sensitive to the histone deacetylase inhibitor trichostatin A (TSAS) accounts for 70%. Both pathways are required for greater than 90% of the response for some target genes. Our findings suggest that a novel functional interaction between the protein acetylases CBP and p300, and deacetylases, is essential for nearly all HIF-responsive transcription.
Keywords:
- CBP,
- CH1,
- HIF,
- hypoxia,
- p300
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