Cross-talks in the p53 family - Delta Np63 is an anti-apoptotci target for Delta Np73 alpha and p53 gain-of-function mutants

摘要

The p53 family of transcription factors plays a pivotal role in the control of the cellular response to DNA damaging agents. In addition to pro-apoptotic molecules such as p53, TAp73 and TAp63, this gene family also encodes for the anti-apoptotic molecules Delta Np73, Delta Np63, Delta Np53, and p53 mutants are often found in tumor cells, that have the role to limit and to modulate the pro-apoptotic side of the family. The ratio between the different members of the family is critical to make the life or death decision following DNA damage and is tightly regulated by post-translational and transcriptional mechanisms. In this study we have uncovered a novel positive feedback that involves the transcriptional activation of the anti-apoptotic molecule Delta Np63 by the anti-apoptotic molecules Delta Np73 and mutant p53, and that is put into motion upon treatment with a subset of DNA damaging agents such as Doxorubicin and 5-FU. Delta Np73 and mutant p53 associate with the Delta Np63 promoter inducing its transcription and this is enhanced by doxorubicin treatment. Furthermore we have observed that Delta Np73- and mutp53-mediated activation of the Delta Np63 promoter requires the functionality of the proximal CCAAT boxes of this promoter, being hampered by mutation of CCAAT boxes or by dominant negative NFYA expression. This mechanism may serve as an additional control of the response of a normal cell to DNA damage or as an anti-apoptotic barrier of cancer cells subjected to DNA damage.