Upregulation of ATBF1 by progesterone-PR signaling and its functional implication in mammary epithelial cells
Upregulation of ATBF1 by progesterone-PR signaling and its functional implication in mammary epithelial cells
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DOI：
10.1016/j.bbrc.2012.11.009
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发表时间：
2013-01-04
影响因子：
3.1
通讯作者：
Dong, Jin-Tang
中科院分区：
文献类型：
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作者：
Li, Mei;Zhao, Dan;Dong, Jin-Tang
孕酮(PG)是乳腺发育和肿瘤发生过程中的一种必需的类固醇激素，包括上皮干细胞/祖细胞的维持。PG通过与孕激素受体(PR)的相互作用发挥作用，PG-PR信号被认为是由关键的转录因子介导的，这些转录因子在很大程度上是未知的。在这项研究中，我们已经确定ATBF1转录因子是乳腺上皮细胞PG-PR信号的转录靶点。PG处理显著增加了培养细胞和乳腺组织中ATBF1的mRNA和蛋白表达。正如预期的那样，ATBF1的诱导是PR依赖的，因为它只发生在PR阳性的细胞中，而不发生在PR阴性的细胞中，而PG拮抗剂RU-486或RNAi介导的PR下调预先阻断了PG对ATBF1的上调。启动子-报告和芯片实验进一步表明PG激活的PR直接与ATBF1启动子结合，诱导其转录。阻止ATBF1诱导抑制PG促进祖细胞转化的功能，Matrigel培养试验中的克隆形成和干细胞标记CD49f和CD44的表达表明。这些发现表明，ATBF1在乳腺上皮细胞PG-PR信号通路中起着关键作用。(C)2012 Elsevier Inc.保留所有权利。
Progesterone (Pg) is an essential steroid hormone during mammary gland development and tumorigenesis, including the maintenance of epithelial stem/progenitor cells. Pg functions through interaction with the progesterone receptors (PR) and Pg-PR signaling is thought to be mediated by key transcription factors, which are largely unidentified. In this study, we have identified the ATBF1 transcription factor as a transcriptional target of Pg-PR signaling in mammary epithelial cells. Pg treatment dramatically increased ATBF1 expression at both mRNA and protein levels in cultured cells and mammary tissues. As expected, the induction of ATBF1 was PR-dependent, as it only occurred in PR-positive but not in PR-negative cells, and pretreatment with the Pg antagonist RU-486 or RNAi-mediated knockdown of PR abolished the upregulation of ATBF1 by Pg. Promoter-reporter and ChIP assays further showed that Pg-activated PR directly binds to the ATBF1 promoter to induce its transcription. Prevention of ATBF1 induction inhibited the function of Pg in promoting progenitor cell transition, as indicated by colony formation in a Matrigel culture assay and expression of stem cell markers CD49f and CD44. These findings suggest that ATBF1 plays a crucial role in the Pg-PR signaling pathway in mammary epithelial cells. (C) 2012 Elsevier Inc. All rights reserved.