Mouse double minute 2 associates with chromatin in the presence of p53 and is released to facilitate activation of transcription.
Mouse double minute 2 associates with chromatin in the presence of p53 and is released to facilitate activation of transcription.
复制标题
小鼠双分钟 2 在 p53 存在的情况下与染色质结合并被释放以促进转录激活。
DOI：
10.1158/0008-5472.can-05-1381
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发表时间：
2006
期刊：
影响因子：
11.2
通讯作者：
Bargonetti,Jill
中科院分区：
文献类型：
--
作者：
White,DavidE;Talbott,KathrynE;Arva,NicoletaC;Bargonetti,Jill
肿瘤抑制因子 p53 是一种有效的转录因子，其介导转录的能力通过与癌蛋白小鼠双分钟 2 (Mdm2) 的相互作用而受到抑制。本研究验证了 Mdm2 通过与染色质相关 p53 结合来抑制正常生长细胞中 p53 反应的假设。使用染色质免疫沉淀，我们发现在表达 p53 的人类细胞系中，Mdm2 与 p53 一起定位在 waf1 和 mdm2 基因上的响应元件上，但在缺乏 p53 表达的细胞系中则不然，表明 Mdm2 以 p53 依赖性方式被招募到 DNA 区域。有趣的是，我们的结果表明，当 p53 诱导的转录通过 DNA 损伤或通过 p53 的受控过度表达而激活时，与 waf1 和 mdm2 基因上的 p53 响应元件相关的 Mdm2 蛋白减少。通过添加破坏 p53-Mdm2 相互作用的小分子抑制剂或小干扰 RNA tomdm2，观察到 p53 转录活性在 p53 蛋白水平增加之前快速激活。这些发现表明 Mdm2 与 p53 一起短暂定位在反应元件上，并表明潜在的 p53 是由 Mdm2 招募到染色质的结果。 （癌症研究 2006 年；66(7)：3463-70）
The tumor suppressor p53 is a potent transcription factor of which the ability to mediate transcription is inhibited through an interaction with the oncoprotein mouse double minute 2 (Mdm2). The present study has tested the hypothesis that Mdm2 inhibits the p53 response in normally growing cells by binding to chromatin-associated p53. Using chromatin immunoprecipitation, we show that Mdm2 localizes with p53 at its responsive elements on thewaf1andmdm2genes in human cell lines expressing p53, but not in cell lines lacking p53 expression, indicating that Mdm2 is recruited to regions of DNA in a p53-dependent manner. Interestingly, our results show a decrease of Mdm2 protein associated with p53-responsive elements on thewaf1andmdm2genes when p53-induced transcription is activated either by DNA damage or through controlled overexpression of p53. Rapid activation of p53 transcriptional activity before increasing p53 protein levels was observed with addition of either small-molecule inhibitors to disrupt the p53-Mdm2 interaction or small interfering RNA tomdm2. These findings indicate Mdm2 transiently localizes with p53 at responsive elements and suggest that latent p53 results from the recruitment of Mdm2 to chromatin. (Cancer Res 2006; 66(7): 3463-70)