Transcriptional repression of epithelial cell adhesion molecule contributes to p53 control of breast cancer invasion.
Transcriptional repression of epithelial cell adhesion molecule contributes to p53 control of breast cancer invasion.
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DOI：
10.1158/0008-5472.can-08-2708
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Gillanders WE
中科院分区：
文献类型：
--
作者：
Sankpal NV;Willman MW;Fleming TP;Mayfield JD;Gillanders WE
p53是一种肿瘤抑制基因，在细胞周期调节、凋亡和维持基因组稳定性方面具有明确的作用。最近的证据表明，p53也可能有助于调节迁移和入侵。上皮细胞粘附分子（EpCAM）是一种跨膜糖蛋白，在大多数人类上皮癌（包括乳腺癌和结直肠癌）中过表达。我们通过染色质免疫沉淀试验证明，p53与EpCAM基因内的候选p53结合位点相互作用。在功能获得和功能丧失实验系统中证实了p53介导的EpCAM转录抑制。野生型p53的诱导与EpCAM表达的显著剂量依赖性降低相关;相反，p53的特异性消融与EpCAM表达的显著增加相关。在功能水平上，p53表达的特异性消融与乳腺癌侵袭增加相关，并且这种作用通过伴随的EpCAM表达的特异性消融而消除。总之，这些生物化学和功能数据首次证明：（1）野生型p53蛋白结合EpCAM基因内的反应元件，并负调节EpCAM表达，和（2）EpCAM的转录抑制有助于p53控制乳腺癌侵袭。
p53 is a tumor suppressor gene with well-characterized roles in cell cycle regulation, apoptosis and the maintenance of genome stability. Recent evidence suggests that p53 may also contribute to the regulation of migration and invasion. Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that is overexpressed in the majority of human epithelial carcinomas, including breast and colorectal carcinomas. We demonstrate by chromatin immunoprecipitation assays that p53 interacts with a candidate p53 binding site within the EpCAM gene. p53-mediated transcriptional repression of EpCAM was confirmed in gain-of-function, and loss-of-function experimental systems. Induction of wildtype p53 was associated with a significant dose-dependent decrease in EpCAM expression; conversely, specific ablation of p53 was associated with a significant increase in EpCAM expression. At the functional level, specific ablation of p53 expression is associated with increased breast cancer invasion, and this effect is abrogated by concomitant specific ablation of EpCAM expression. Taken together, these biochemical and functional data are the first demonstration that (1) wildtype p53 protein binds to a response element within the EpCAM gene and negatively regulates EpCAM expression, and (2) transcriptional repression of EpCAM contributes to p53 control of breast cancer invasion.