TAp63 induces senescence and suppresses tumorigenesis in vivo

Guo, X., Keyes, W. M., Papazoglu, C., Zuber, J., Li, W., Lowe, S. W., Vogel, H., Mills, A. A. (December 2009) TAp63 induces senescence and suppresses tumorigenesis in vivo. Nat Cell Biol, 11 (12). 1451–1457.

Abstract

p63 is distinct from its homologue p53 in that its role as a tumour suppressor is controversial, an issue complicated by the existence of two classes of p63 isoforms1. Here we show that TAp63 isoforms are robust mediators of senescence that inhibit tumorigenesis in vivo. Whereas gain of TAp63 induces senescence, loss of p63 enhances sarcoma development in mice lacking p53. Using a new TAp63-specific conditional mouse model, we demonstrate that TAp63 isoforms are essential for Ras-induced senescence, and that TAp63 deficiency increases proliferation and enhances Ras-mediated oncogenesis in the context of p53 deficiency in vivo. TAp63 induces senescence independently of p53, p19Arf and p16Ink4a, but requires p21Waf/Cip1 and Rb. TAp63-mediated senescence overrides Ras-driven transformation of p53-deficient cells, preventing tumour initiation, and doxycycline-regulated expression of TAp63 activates p21Waf/Cip1, induces senescence and inhibits progression of established tumours in vivo. Our findings demonstrate that TAp63 isoforms function as tumour suppressors by regulating senescence through p53-independent pathways. The ability of TAp63 to trigger senescence and halt tumorigenesis irrespective of p53 status identifies TAp63 as a potential target of anti-cancer therapy for human malignancies with compromised p53

Item Type:	Paper
Subjects:	diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p63 organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence
CSHL Authors:	Guo, Xuecui Keyes, William M. Li, Wangzhi Lowe, Scott W. Mills, Alea A. Papazoglu, Cristian Zuber, Johannes
Communities:	CSHL labs > Lowe lab CSHL labs > Mills lab CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > DNA Sequencing Service CSHL Cancer Center Shared Resources > Flow Cytometry Service CSHL Cancer Center Shared Resources > Gene Targeting Service CSHL Cancer Center Shared Resources > Microscopy Service
Depositing User:	Matt Covey
Date:	December 2009
Date Deposited:	19 Feb 2013 19:40
Last Modified:	30 Dec 2014 16:18
PMCID:	PMC2920298
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/27466

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