Dual regulation of c-Myc by p300 via acetylation-dependent control of Myc protein turnover and coactivation of Myc-induced transcription
Dual regulation of c-Myc by p300 via acetylation-dependent control of Myc protein turnover and coactivation of Myc-induced transcription
复制标题
DOI：
10.1128/mcb.25.23.10220-10234.2005
复制
发表时间：
2005-12-01
影响因子：
5.3
通讯作者：
Martinez, E
中科院分区：
文献类型：
--
作者：
Faiola, F;Liu, XH;Martinez, E
c-Myc癌蛋白（Myc）通过与DNA结合伴侣Max一起调节基因转录来控制细胞命运。虽然Max缺乏转录调节结构域，但Myc的N末端含有转录激活结构域（NTA），其募集含有组蛋白乙酰转移酶（HAT）GCN 5和Tip 60的辅因子复合物。在这里，我们报告了一种新的功能之间的相互作用Myc？和p300辅激活蛋白乙酰转移酶。我们表明，p300协会与Myc在哺乳动物细胞和体外通过直接相互作用与Myc的β-残基1至110和乙酰化Myc在体内的TAD依赖性的方式在几个赖氨酸残基之间的β-和DNA结合结构域。此外，Myc：Max复合物在体外被p300和GCN 5差异乙酰化，并且不被Tip 60乙酰化，这表明这些乙酰转移酶具有不同的功能。而p300和CBP可以稳定Myc独立的乙酰化，p300介导的乙酰化的结果增加Myc营业额。此外，p300作为一个辅激活因子，被Myc募集到人端粒酶逆转录酶基因的启动子，p300/CBP以HAT结构域依赖的方式刺激Myc TAD依赖的转录。我们的研究结果表明p300/CBP在Myc调控中的双重作用：作为Myc共激活剂稳定Myc，并通过直接Myc乙酰化作为Myc不稳定的诱导剂。
The c-Myc oncoprotein (Myc) controls cell fate by regulating gene transcription in association with a DNA-binding partner, Max. While Max lacks a transcription regulatory domain, the N terminus of Myc contains a transcription activation domain (TAD) that recruits cofactor complexes containing the histone acetyltransferases (HATs) GCN5 and Tip60. Here, we report a novel functional interaction between Myc TAD and the p300 coactivator-acetyltransferase. We show that p300 associates with Myc in mammalian cells and in vitro through direct interactions with Myc TAD residues 1 to 110 and acetylates Myc in a TAD-dependent manner in vivo at several lysine residues located between the TAD and DNA-binding domain. Moreover, the Myc:Max complex is differentially acetylated by p300 and GCN5 and is not acetylated by Tip60 in vitro, suggesting distinct functions for these acetyltransferases. Whereas p300 and CBP can stabilize Myc independently of acetylation, p300-mediated acetylation results in increased Myc turnover. In addition, p300 functions as a coactivator that is recruited by Myc to the promoter of the human telomerase reverse transcriptase gene, and p300/CBP stimulates Myc TAD-dependent transcription in a HAT domain-dependent manner. Our results suggest dual roles for p300/CBP in Myc regulation: as a Myc coactivator that stabilizes Myc and as an inducer of Myc instability via direct Myc acetylation.