TY - JOUR
T1 - P53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice
AU - Begus-Nahrmann, Yvonne
AU - Lechel, André
AU - Obenauf, Anna C.
AU - Nalapareddy, Kodandaramireddy
AU - Peit, Elvira
AU - Hoffmann, Eva
AU - Schlaudraff, Falk
AU - Liss, Birgit
AU - Schirmacher, Peter
AU - Kestler, Hans
AU - Danenberg, Esther
AU - Barker, Nick
AU - Clevers, Hans
AU - Speicher, Michael R.
AU - Rudolph, K. Lenhard
N1 - Funding Information:
We thank S. Robine (Institute Curie-CNRS, Paris) for providing villin-Cre-ERT2 mice and A. Berns (The Netherlands Cancer Institute, Amsterdam) for providing conditional p53 knockout mice. We thank J. Jonkers ((The Netherlands Cancer Institute, Amsterdam ) for providing the BAC clones for chromosome FISH. We thank G. Schütz (German Cancer Research Center, Heidelberg) for providing self-made Cre antibody. We thank C. Günes for critical reading of the manuscript. This project was supported by funding from the Deutsche Forschungsgemeinschaft (KFO 167, RU745/10-1), by the Deutsche Krebshilfe e.V. (consortium grant on tumor stem cells) and by the European Union (GENINCA, Telomarker). K.L.R. and M.R.S. are both supported by the European Union (GENINCA, contract number 202230).
PY - 2009/10
Y1 - 2009/10
N2 - Telomere dysfunction limits the proliferative capacity of human cells and induces organismal aging by activation of p53 and p21 (refs. 1, 2, 3, 4, 5, 6). 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.
AB - Telomere dysfunction limits the proliferative capacity of human cells and induces organismal aging by activation of p53 and p21 (refs. 1, 2, 3, 4, 5, 6). 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.
UR - http://www.scopus.com/inward/record.url?scp=70349559751&partnerID=8YFLogxK
U2 - 10.1038/ng.426
DO - 10.1038/ng.426
M3 - Article
C2 - 19718028
AN - SCOPUS:70349559751
SN - 1061-4036
VL - 41
SP - 1138
EP - 1143
JO - Nature Genetics
JF - Nature Genetics
IS - 10
ER -