p63 deficiency activates a program of cellular senescence and leads to accelerated aging

The p53 tumor suppressor plays a key role in organismal aging. A cellular mechanism postulated to drive the aging process is cellular senescence, mediated in part by p53. Although senescent cells accumulate in elderly individuals, most studies have relied on correlating in vitro senescence assays with in vivo phenotypes of aging. Here, using two different mouse models in which the p53-related protein p63 is compromised, we demonstrate that cellular senescence and organismal aging are intimately linked and that these processes are mediated by p63 loss. We found that p63(+/-) mice have a shortened life span and display features of accelerated aging. Both germline and somatically induced p63 deficiency activates widespread cellular senescence with enhanced expression of senescent markers SA-β-gal, PML, and p16(INK4a). Using an inducible tissue-specific p63 conditional model, we further show that p63 deficiency induces cellular senescence and causes accelerated aging phenotypes in the adult. Our results thus suggest a causative link between cellular senescence and aging in vivo, and demonstrate that p63 deficiency accelerates this process

ΔNp63α is an oncogene that targets chromatin remodeler Lsh to drive skin stem cell proliferation and tumorigenesis

The p53 homolog p63 is essential for development, yet its role in cancer is not clear. We discovered that p63 deficiency evokes the tumor-suppressive mechanism of cellular senescence, causing a striking absence of stratified epithelia such as the skin. Here we identify the predominant p63 isoform, ΔNp63α, as a protein that bypasses oncogene-induced senescence to drive tumorigenesis in vivo. Interestingly, bypass of senescence promotes stem-like proliferation and maintains survival of the keratin 15-positive stem cell population. Furthermore, we identify the chromatin-remodeling protein Lsh as a new target of ΔNp63α that is an essential mediator of senescence bypass. These findings indicate that ΔNp63α is an oncogene that cooperates with Ras to promote tumor-initiating stem-like proliferation and suggest that Lsh-mediated chromatin-remodeling events are critical to this process.We thank Johannes Zuber, Michael Hemann, and Scott Lowe for assistance and advice; Yuri Lazebnik and Dominik Duelli for DMBA-treated tissues; Chris Johns and Sohail Khan for microarray analysis; and Leif Ellisen and James W. Rocco for HNSCC cell lines. W.M.K. was funded by the Spanish Ministry of Science and Innovation (Plan Nacional –SAF2010-18829). A.A.M. was funded by an ACS Research Scholar Award (RSG-06-190-01-MGO)

TAp63 induces senescence and suppresses tumorigenesis in vivo

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 p5