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

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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.