Defining the role of Notch signalling in the formation of Cholangiocarcinoma (B06)

项目B06(定义Notch信号在胆管癌变中的作用)研究了DNA损伤反应(DDR)在胆管癌变中的机制和作用；研究表明，Notch胞内域(NICD)的激活可诱导高水平的细胞周期蛋白E、低水平的细胞周期蛋白激酶抑制物p27kip1和遗传不稳定性，从而促进胆管癌变。P27与DDR基因rad17形成复合体，阻止ATM激酶的过早磷酸化，从而阻止G1期的异常同源重组。这一新的DDR机制表明，p27缺陷CCA对DNA损伤药物具有很强的敏感性，可能涉及外部机制。此外，该项目还表明，在CCA的形成中，P53的丢失与Notch协同作用，并且令人惊讶的是，P53阻止了p27的翻译。在新的资助期，该项目将确定p53如何阻止p27翻译的机制，以及p27如何通过可能涉及核因子-kB信号的内在和潜在外在机制来调节CCA微环境。

Project B06 (Malek; Defining the role of Notch signalling in the formation of Cholangiocarcinoma) addresses the mechanism and role of DNA damage response (DDR) in cholangiocarcinogenesis; it has shown that Notch intracellular domain (NICD) activation induces high levels of cyclin E, low levels of the cyclin kinase inhibitor p27kip1 and genetic instability and thereby promotes cholangiocarcinogenesis. P27 was shown to complex with the DDR gene rad17, preventing premature phosphorylation of the ATM kinase and thus aberrant homologous recombination in G1 phase. This new DDR-mechanism suggests strong sensitivity of p27 deficient CCAs to DNA damaging drugs potentially involving extrinsic mechanisms. In addition, the project showed that loss of p53 cooperates with Notch in CCA formation, and surprisingly p53 prevents p27 translation. In the new funding period the project will determine the mechanism how p53 blocks p27 translation and how p27 modulates the CCA microenvironment by intrinsic and potentially extrinsic mechanisms that may involve NF-kB signalling.