p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice.
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.
Begus-Nahrmann
Yvonne
Y
Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, University of Ulm, Ulm, Germany.
Lechel
André
A
Obenauf
Anna C
AC
Nalapareddy
Kodandaramireddy
K
Peit
Elvira
E
Hoffmann
Eva
E
Schlaudraff
Falk
F
Liss
Birgit
B
Schirmacher
Peter
P
Kestler
Hans
H
Danenberg
Esther
E
Barker
Nick
N
Clevers
Hans
H
Speicher
Michael R
MR
Rudolph
K Lenhard
KL
D000375:Aging / Q000502:physiology*; D000818:Animals; D002453:Cell Cycle; D043171:Chromosomal Instability; D004249:DNA Damage; D017353:Gene Deletion; D016678:Genome; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D016615:Telomere / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D016159:Tumor Suppressor Protein p53