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

  1. William M. Keyes1,
  2. Ying Wu1,
  3. Hannes Vogel2,
  4. Xuecui Guo1,
  5. Scott W. Lowe1, and
  6. Alea A. Mills1,3
  1. 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; 2Stanford University, Stanford, California 94305, USA

Abstract

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 p16INK4a. 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.

Keywords

Footnotes

  • Supplemental material is available at http://www.genesdev.org.

  • Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.342305.

  • 3 Corresponding author.

    3 E-MAIL mills{at}cshl.edu; FAX (516) 367-8874.

    • Accepted July 5, 2005.
    • Received March 5, 2005.
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