Molecular basis of E-cadherin transcriptional regulation

描述(由申请人提供)： 我们对癌症发生的了解远远超过了我们对肿瘤进展的了解。细胞黏附分子E-钙粘附素参与肿瘤的形成和侵袭。DNA结合蛋白Snail和Slug介导E-钙粘蛋白的转录抑制，并调节癌症发生和细胞存活的各个方面。虽然对Snail和Slug的生物学功能已经了解很多，但Snail和Slug介导的转录抑制的分子机制还不是很清楚。这项研究的目的是在E-钙粘蛋白启动子的背景下确定Snail和Slug抑制的分子机制。首先，将在体外重组E-钙粘蛋白启动子的特异性激活，然后进行生化研究，以阐明蜗牛和E-钙粘蛋白的鼻涕状抑制的机制。最后，将进行体内研究，以补充生化方法，并检查活细胞中E-钙粘附素的转录调控。这些研究将提供对蜗牛和鼻涕虫抑制和E-钙粘素沉默的基础的洞察，并可能潜在地识别肿瘤建立和侵袭的关键成分。

DESCRIPTION (provided by applicant): Our understanding of cancer initiation far exceeds our knowledge of tumor progression. The cell adhesion molecule E-cadherin contributes to aspects of tumor formation and invasion. The DNA-binding proteins Snail and Slug mediate E-cadherin transcriptional repression, and regulate aspects of carcinogenesis and cell survivability. While much has been learned regarding Snail and Slug biological function, the molecular mechanisms of Snail and Slug mediated transcriptional repression are not well understood. The studies in this proposal aim to determine the molecular mechanisms of Snail and Slug repression in the context of the E-cadherin promoter. First, specific activation of the E-cadherin promoter will be reconstituted in vitro, followed by biochemical studies to elucidate the mechanisms of Snail and Slug repression of E-cadherin. Finally, studies in vivo will be performed to complement the biochemical approaches, and examine E-cadherin transcriptional regulation in living cells. These studies will provide insight into the basis of Snail and Slug repression and E-cadherin silencing, and may potentially identify key components of tumor establishment and invasion.