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p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice

Begus-Nahrmann, Y. and Lechel, A. and Obenauf, A. C. and Nalapareddy, K. and Peit, E. and Hoffmann, E. and Schlaudraff, F. and Liss, B. and Schirmacher, P. and Kestler, H. and Danenberg, E.M. and Barker, N. and Clevers, H. and Speicher, M. R. and Rudolph, K. L. (2009) p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice. Nature Genetics, 41, 1138-43. ISSN 1061-4036.

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Official URL: http://dx.doi.org/10.1038/ng.426

Abstract

Telomere dysfunction limits the proliferative capacity of human cells and induces organismal aging by activation of p53 and p21. Although deletion of p21 elongates the lifespan of telomere-dysfunctional mice, a direct analysis of p53 in telomere-related aging has been hampered by early tumor formation in p53 knockout mice. Here we analyzed the functional consequences of conditional p53 deletion. Intestinal deletion of p53 shortened the lifespan of telomere-dysfunctional mice without inducing tumor formation. In contrast to p21 deletion, the deletion of p53 impaired the depletion of chromosomal-instable intestinal stem cells in aging telomere-dysfunctional mice. These instable stem cells contributed to epithelial regeneration leading to an accumulation of chromosomal instability, increased apoptosis, altered epithelial cell differentiation and premature intestinal failure. Together, these results provide the first experimental evidence for an organ system in which p53-dependent mechanisms prevent tissue destruction in response to telomere dysfunction by depleting genetically instable stem cells.

Item Type:Article
Institutes:Hubrecht Instituut
ID Code:7004
Deposited On:25 Jan 2010 01:00
Last Modified:13 Oct 2010 12:51

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