Chen H, Lin R J, Xie W, Wilpitz D, Evans R M
The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Cell. 1999 Sep 3;98(5):675-86. doi: 10.1016/s0092-8674(00)80054-9.
Nuclear receptors have been postulated to regulate gene expression via their association with histone acetylase (HAT) or deacetylase complexes. We report that hormone induces dramatic hyperacetylation at endogenous target genes through the HAT activity of p300/CBP. Unexpectedly, this hyperacetylation is transient and coincides with attenuation of hormone-induced gene activation. In exploring the underlying mechanism, we found that the acetylase ACTR can be acetylated by p300/CBP. The acetylation neutralizes the positive charges of two lysine residues adjacent to the core LXXLL motif and disrupts the association of HAT coactivator complexes with promoter-bound estrogen receptors. These results provide strong in vivo evidence that histone acetylation plays a key role in hormone-induced gene activation and define cofactor acetylation as a novel regulatory mechanism in hormonal signaling.
核受体被认为可通过与组蛋白乙酰转移酶（HAT）或去乙酰化酶复合物结合来调节基因表达。我们报告称，激素通过p300/CBP的HAT活性在内源靶基因上诱导显著的超乙酰化。出乎意料的是，这种超乙酰化是短暂的，并且与激素诱导的基因激活减弱相吻合。在探究其潜在机制时，我们发现乙酰转移酶ACTR可被p300/CBP乙酰化。这种乙酰化中和了核心LXXLL基序相邻的两个赖氨酸残基的正电荷，并破坏了HAT共激活复合物与启动子结合的雌激素受体之间的结合。这些结果提供了强有力的体内证据，表明组蛋白乙酰化在激素诱导的基因激活中起关键作用，并将辅因子乙酰化定义为激素信号传导中的一种新型调节机制。
