Sayeed Aejaz, Konduri Santhi D, Liu Wensheng, Bansal Sanjay, Li Fengzhi, Das Gokul M
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Cancer Res. 2007 Aug 15;67(16):7746-55. doi: 10.1158/0008-5472.CAN-06-3724.
Estrogen receptor alpha (ERalpha) and tumor suppressor protein p53 exert opposing effects on cellular proliferation. As a transcriptional regulator, p53 is capable of activating or repressing various target genes. We have previously reported that ERalpha binds directly to p53, leading to down-regulation of transcriptional activation by p53. In addition to transcriptional activation, transcriptional repression of a subset of target genes by p53 plays important roles in diverse biological processes, such as apoptosis. Here, we report that ERalpha inhibits p53-mediated transcriptional repression. Chromatin immunoprecipitation assays reveal that ERalpha interacts in vivo with p53 bound to promoters of Survivin and multidrug resistance gene 1, both targets for transcriptional repression by p53. ERalpha binding to p53 leads to inhibition of p53-mediated transcriptional regulation of these genes in human cancer cells. Transcriptional derepression of Survivin by ERalpha is dependent on the p53-binding site on the Survivin promoter, consistent with our observation that p53 is necessary for ERalpha to access the promoters. Importantly, mutagenic conversion of this site to an activation element enabled ERalpha to repress p53-mediated transcriptional activation. Further, RNA interference-mediated knockdown of ERalpha resulted in reduced Survivin expression and enhanced the propensity of MCF-7 cells to undergo apoptosis in response to staurosporine treatment, an effect that was blocked by exogenous expression of Survivin. These results unravel a novel mechanism by which ERalpha opposes p53-mediated apoptosis in breast cancer cells. The findings could have translational implications in developing new therapeutic and prevention strategies against breast cancer.
雌激素受体α（ERα）和肿瘤抑制蛋白p53对细胞增殖具有相反的作用。作为一种转录调节因子，p53能够激活或抑制各种靶基因。我们之前报道过，ERα直接与p53结合，导致p53介导的转录激活作用下调。除了转录激活作用外，p53对一部分靶基因的转录抑制作用在多种生物学过程（如细胞凋亡）中发挥着重要作用。在此，我们报道ERα抑制p53介导的转录抑制作用。染色质免疫沉淀分析表明，ERα在体内与结合在生存素（Survivin）和多药耐药基因1启动子上的p53相互作用，这两个基因都是p53转录抑制的靶标。ERα与p53的结合导致人癌细胞中p53介导的这些基因转录调控受到抑制。ERα对生存素的转录去抑制作用依赖于生存素启动子上的p53结合位点，这与我们观察到的p53是ERα进入启动子所必需的结果一致。重要的是，将该位点诱变转化为激活元件可使ERα抑制p53介导的转录激活作用。此外，RNA干扰介导的ERα敲低导致生存素表达降低，并增强了MCF-7细胞对星形孢菌素处理诱导凋亡的倾向，而生存素的外源性表达可阻断这种效应。这些结果揭示了一种新机制，通过该机制ERα在乳腺癌细胞中对抗p53介导的细胞凋亡。这些发现可能对开发针对乳腺癌的新治疗和预防策略具有转化意义。
