506 Molecular mechanisms of p53 activity in stem cell-driven skin tumour initiation

Abstract

TP53 (p53) is the most frequently mutated gene and altered in approximately 50% of human cancer leading to loss or aberrant activation of p53. Tumours lacking p53 mutations often display inactivated wild-type p53 due to modulation of protein interactions resulting in p53 degradation. Functionally, p53 acts as an essential transcriptional factor controlling the response to several different cellular stresses including DNA damage, hypoxia and oncogene activation. It is well known that common environmental assaults, including UV irradiation cause p53 modifications, promoting tumorigenesis in mammalian skin. Increasing evidence suggest that restoring normal p53 function will be highly beneficial for cancer therapy. Therefore, it is important to gain better insights into the regulation of p53 stability in the context of oncogenic mutations in skin cancer. In this context, our previous work uncovered important stem cell-specific functions of p53 protecting from tumour initiation and guaranteeing tissue maintenance. Here, we decipher the underlying molecular mechanism of p53-induced stem cell responses and explore the mechanistic link between p53 and b-catenin/Lef1 interaction in stem cell-driven skin cancer. Using a transgenic mouse model for mutant Lef1-driven tumourigenesis, thereby mimicking Lef1 mutations found in human skin tumours, we demonstrate that mutant Lef1 induces tumours by interfering with stem cell-specific gatekeeper functions normally preventing tumour initiation. Mechanistically, mutant Lef1 disturbs p53 responses by antagonizing ATM-Chk2-dependent p53 stabilization. Most importantly, modulating the level of p53 activity in the context of tumour initiation had a great impact on the cell-of-origin and the phenotype of epidermal tumours. In conclusion, our work identified novel aspects of p53 in stem cell-driven skin tumour initiation, is providing new mechanistic insights into p53 activity and is connecting p53 and b-catenin/Lef1 signalling and thus addresses important issues highly relevant for translational skin research.