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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >ANCCA, an estrogen-regulated AAA+ ATPase coactivator for ERα, is required for coregulator occupancy and chromatin modification
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ANCCA, an estrogen-regulated AAA+ ATPase coactivator for ERα, is required for coregulator occupancy and chromatin modification

机译：ANCCA是雌激素调节的ERα的AAA + ATPase共激活剂，对于调节剂占有率和染色质修饰是必需的

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摘要

AAA+ proteins play crucial roles in diverse biological processes via their ATPase-driven remodeling of macromolecular complexes. Here we report our identification of an evolutionary conserved AAA+ protein, ANCCA/pro2000, endowed with a bromodomain that is strongly induced by estrogen in human breast cancer cells and is a direct target of protooncogene ACTR/AIB1/SRC-3. We found that ANCCA associates directly with estrogen-bound estrogen receptor (ER) α and ACTR. It is selectively recruited, upon estrogen stimulation, to a subset of ERα target genes including cyclin D1, c-myc, and E2F1 and is required for their estrogen-induced expression as well as breast cancer cell proliferation. Further studies indicate that ANCCA binds and hydrolyzes ATP and is critical for recruitment of coregulator CBP and histone hyper acetylation at the ER target chromatin. Moreover, mutations at the ATP binding motifs rendered ANCCA defective as a coactivator in mediating estrogen induction of gene expression. Together, our findings reveal an unexpected layer of regulatory mechanism in hormone signaling mediated by ANCCA and suggest that hormone-induced assembly of transcriptional coregulator complexes at chromatin is a process facilitated by AAA+ ATPase proteins.
机译：AAA +蛋白通过其ATPase驱动的大分子复合物重塑在多种生物过程中发挥关键作用。在这里，我们报告我们鉴定的进化保守的AAA +蛋白ANCCA / pro2000，具有由人乳腺癌细胞中的雌激素强烈诱导的溴结构域，并且是原癌基因ACTR / AIB1 / SRC-3的直接靶标。我们发现ANCCA与雌激素结合的雌激素受体（ER）α和ACTR直接相关。在雌激素刺激下，它被选择性地募集到ERα靶基因的一个子集，包括细胞周期蛋白D1，c-myc和E2F1，它们是雌激素诱导表达以及乳腺癌细胞增殖所必需的。进一步的研究表明，ANCCA结合并水解ATP，对于在ER目标染色质上募集共调剂CBP和组蛋白高度乙酰化至关重要。此外，ATP结合基序处的突变使ANCCA在介导雌激素诱导基因表达中作为辅助活化剂存在缺陷。在一起，我们的发现揭示了由ANCCA介导的激素信号传导中意想不到的调节机制层，并表明激素诱导的染色质转录共调节复合物的组装是AAA + ATPase蛋白促进的过程。

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