Kasper Lawryn H, Boussouar Fayçal, Boyd Kelli, Xu Wu, Biesen Michelle, Rehg Jerold, Baudino Troy A, Cleveland John L, Brindle Paul K
Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
EMBO J. 2005 Nov 16;24(22):3846-58. doi: 10.1038/sj.emboj.7600846. Epub 2005 Oct 20.
The C-terminal activation domain (C-TAD) of the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha 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 (DeltaCH1) 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 approximately 35-50% of global HIF-1-responsive gene expression, whereas another HIF transactivation mechanism that is sensitive to the histone deacetylase inhibitor trichostatin A (TSA(S)) accounts for approximately 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.
缺氧诱导转录因子HIF-1α和HIF-2α的C端激活结构域（C-TAD）与相关转录共激活因子CREB结合蛋白（CBP）和p300的CH1结构域结合，这种氧调节的相互作用被认为对缺氧反应性转录至关重要。然而，CH1结构域在体内的作用尚不清楚。我们构建了CBP和p300的CH1结构域缺失（DeltaCH1）的突变小鼠，这些缺失消除了它们与C-TAD的相互作用，结果表明CBP和p300的CH1结构域在遗传上是非冗余的，并且对于C-TAD反式激活功能是不可或缺的。令人惊讶的是，CH1结构域仅对平均约35%-50%的整体HIF-1反应性基因表达是必需的，而另一种对组蛋白脱乙酰酶抑制剂曲古抑菌素A（TSA(S)）敏感的HIF反式激活机制约占70%。对于某些靶基因，两种途径对于超过90%的反应都是必需的。我们的研究结果表明，蛋白乙酰化酶CBP和p300与脱乙酰酶之间的一种新型功能相互作用对于几乎所有HIF反应性转录都是必不可少的。
