Catherin Niemann - A 7

Mechanisms of stem cell-specific gatekeeper functions in cancer initiation

Abstract

The tumor suppressor p53 is frequently mutated in human cancer and tumors lacking p53 mutations often display inactivated wild-type p53 through modulation of protein interactions resulting in p53 protein degradation. To further explore the strategy of restoring normal p53 function for cancer therapy it will be important to better understand the consequences of specific p53 mutations and to gain better insights into the regulation of p53 stability in the context of oncogenic mutations. Recently, our work has identified a novel stem cell-specific p53 gatekeeper function in a mouse model for mutant Lef1-induced skin cancer. Thus, the project aims to decipher the underlying molecular and cellular mechanisms of p53 and ?-catenin/Lef1 interaction in stem cell-driven cancer. In particular, complex genetic mouse models and epidermal cell cultures will be used to unravel how p53 governs stem cell function, including self-renewal and cell differentiation. This study will focus on the impact of the p53-p21-signaling axis on the mechanisms of DNA damage repair, proliferation and prove the importance of defective p53-p21 activity for tumor initiation. More mechanistically, the proposed molecular experiments will unravel how mutant Lef1 alters p53-dependent signaling. In this context, we will test the strategy of restoring p53 in tumors from mutant Lef1 mice as relevant therapy for skin cancer. Importantly, the results will provide fundamental insights into a novel concept of stem cell-specific p53 signaling and its relevance for the process of tumor initiation.

Clinical/medical relevance and sustainability in disease understanding

This project aims to better understand the function and upstream control mechanisms of p53 in the so far unexplored context of stem cell-driven cancer. The study will address how p53 mechanistically integrates with other oncogenic pathways. The results should impact on a concept of restoration of p53 function in skin cancer as a sound therapy option. Finally, deciphering role of stem cell-specific gatekeeper functions for tumor initiation and cancer stem cells in general would be highly beneficial for optimizing cancer treatment strategies.


PD Dr. rer. nat. Catherin Niemann

Institute for Biochemistry and CMMC

PD Dr. rer. nat. Catherin Niemann

Principal Investigator A 7
Co-Coordinator - IPMM Program
Head - Tissue Embedding and Histology Facility

cnieman1@uni-koeln.de

Work +49 221 478 89511

Fax (Work) +49 221 478 86737

CMMC Research Building
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50931 Cologne

Publications - Catherin Niemann

Link to PubMed