Molecular basis of E-cadherin transcriptional regulation

描述（由申请人提供）： 我们对癌症发生的理解远远超过了我们对肿瘤进展的了解。细胞粘附分子E-钙粘蛋白有助于肿瘤形成和侵袭。DNA结合蛋白Snail和Slug介导E-钙粘蛋白的转录抑制，并调节癌发生和细胞存活的各个方面。虽然关于Snail和Slug的生物学功能已经了解了很多，但是Snail和Slug介导的转录抑制的分子机制还没有很好地理解。本研究的目的是确定E-钙粘蛋白启动子对Snail和Slug阻遏作用的分子机制。首先，将在体外重建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E-钙粘蛋白的Snail和Slug抑制机制。 最后，将进行体内研究以补充生物化学方法，并检查活细胞中E-钙粘蛋白的转录调控。这些研究将为Snail和Slug抑制和E-cadherin沉默的基础提供深入了解，并可能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.