转录共激活子TAZ的分子调控机制及其生物学功能的研究

发布时间：2018-01-12 04:36

本文关键词：转录共激活子TAZ的分子调控机制及其生物学功能的研究　出处：《复旦大学》2011年博士论文　论文类型：学位论文

【摘要】：研究发现转录共激活子TAZ促进细胞增殖、细胞迁移和诱导上皮细胞向间充质细胞的转化(EMT)。最近我们的研究表明TAZ受肿瘤抑制信号通路Hippo通路调控。但是作为转录共激活子,TAZ如何通过转录因子调控基因转录并行使生物学功能却还不清楚。通过实验我们发现TEAD转录因子家族成员是介导TAZ生物学功能的重要下游转录因子。阻断TEAD与TAZ的结合或者抑制细胞内源的TEAD的表达,都可以阻断了TAZ促进细胞增殖、细胞迁移和诱导上皮细胞向间充质细胞的转化的生物学功能。同时,我们还发现结缔组织生长因子(CTGF)是转录共激活子TAZ和转录因子TEAD的下游直接靶基因。我们的研究阐明了转录共激活子TAZ和转录因子TEAD的相互作用关系,以及二者的相互作用在转录共激活子TAZ行使生物学功能中的作用机制。转录共激活子TAZ的活性受Hippo通路调控, Hippo通路的激活会促进TAZ从细胞核转运至细胞质中,从而抑制了TAZ与核转录因子的结合。我们的研究发现TAZ的蛋白质降解受SCFβ-TrCP的E3泛素连接酶的调控。β-TrCP与TAZ之间的相互作用受Hippo通路的调控。转录共激活子TAZ被激酶磷酸化后,激酶CKIε接着磷酸化TAZ,从而促进了β-TrCP与TAZ之间的结合。因此,Hippo通路不仅仅促进转录共激活子TAZ滞留在细胞质中,还促进TAZ的蛋白质降解。TAZ的依赖于蛋白酶体的降解对TAZ的生物学功能调控也有着重要作用。转录共激活子TAZ作为受Hippo通路的调控。Hippo通路调控TAZ的活性是通过激酶LATS直接磷酸化TAZ,促进转录共激活子TAZ滞留在细胞质中并且促进TAZ的蛋白质降解。然而转录共激活子TAZ的去磷酸化调控机制以及调控TAZ活性的磷酸酶一直都不清楚。这里我们发现蛋白磷酸酶1(PP1)是调控TAZ活性的磷酸酶。PP1可以去磷酸化TAZ的Ser89位点和Ser311位点,从而促进TAZ的核定位与蛋白稳定性。进一步的,我们还发现肿瘤抑制基因ASPP2可以促进TAZ与PP1的结合,从而调控转录共激活子TAZ的去磷酸化过程。因此,PP1和ASPP2可以调控TAZ的下游靶基因的表达。这一研究阐明了PP1A和ASPP2作为转录共激活子TAZ的正调控因子,促进TAZ的生物学功能。
[Abstract]:It was found that the transcriptional co-activator TAZ promoted cell proliferation. Cell migration and induction of epithelial to mesenchymal cell transformation. Our recent studies have shown that TAZ is regulated by the tumor suppressor signaling pathway Hippo pathway, but as a transcriptional co-activator. It is not clear how TAZ regulates gene transcription and performs biological functions by transcription factors. Through experiments, we found that TEAD transcription factor family members are important downstream transcriptional factors that mediate the biological function of TAZ. Blocking the binding of TEAD to TAZ or inhibiting the expression of endogenous TEAD in cells. Both can block the biological function of TAZ in promoting cell proliferation, cell migration and inducing the transformation of epithelial cells to mesenchymal cells. We also found CTGFs of connective tissue growth factor (CTGF). It is the downstream direct target gene of transcriptional coactivator TAZ and transcription factor TEAD. Our research has clarified the interaction between transcription coactivator TAZ and transcription factor TEAD. And the mechanism of their interaction in the biological function of transcriptional coactivator TAZ. The activity of transcriptional co-activator TAZ is regulated by Hippo pathway, and the activation of Hippo pathway can promote TAZ transport from nucleus to cytoplasm. Our results show that the protein degradation of TAZ is regulated by the E3-ubiquitin ligase of SCF 尾 -TrCP. The phase between 尾 -TrCP and TAZ. The interaction is regulated by the Hippo pathway. The transcriptional co-activator TAZ is phosphorylated by kinase. Kinase CKI 蔚 then phosphorylates TAZs, thus facilitating the binding between 尾 -TrCP and TAZ. Therefore, the Hippo pathway not only stimulates the retention of transcriptional coactivator TAZ in the cytoplasm. The protein degradation of TAZ. TAZ dependent on proteasome degradation also plays an important role in the regulation of biological function of TAZ. Transcriptional co-activator TAZ is regulated by Hippo pathway. Hippo pathway regulates the activity of TAZ through kinase LATS phosphorylation of TAZ. The mechanism of dephosphorylation of transcriptional coactivator TAZ and the phosphatase that regulates the activity of TAZ have been unclear. Chu. Here we find protein phosphatase 1. PP1) is a phosphatase. PP1 that regulates the activity of TAZ. PP1 can dephosphorize TAZ at Ser89 site and Ser311 site. Further, we also found that tumor suppressor gene ASPP2 can promote the binding of TAZ and PP1. Thus regulating the dephosphorylation process of transcriptional co-activator TAZ. PP1 and ASPP2 can regulate the expression of downstream target genes of TAZ. This study elucidates that PP1A and ASPP2 are positive regulators of TAZ transcriptional coactivator. To promote the biological function of TAZ.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2011
【分类号】：R346

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