Introduction: Telomere dysfunction limits the proliferative capacity of human cells and induces organismal aging in mouse models by activation of p53/p21 signaling pathways. While p21 deletion elongated the lifespan of telomere dysfunctional mice, a direct analysis of the functional role of p53 in telomere-related aging has been hampered by early tumor formation in germ-line p53 knockout mice. Aim/Methods: Here we analyzed functional consequences of conditional p53 deletion in the intestinal epithelium on aging of mice with functional or dysfunctional telomeres. Results: Unexpectedly, intestinal deletion of p53 shortened the lifespan of telomere dysfunctional mice without inducing tumor formation. In contrast to p21 deletion, p53 deletion impaired the depletion of chromosomal instable stem cells in the intestine of aging telomere dysfunctional mice. These genetically instable stem cells contributed to epithelial regeneration thereby leading to an accumulation of chromosomal instability, increased apoptosis, and premature intestinal failure. Conclusion: Together, these results provide first experimental evidence that p53 has a unique role in protecting telomere dysfunctional tissues from age related atrophy by depleting genetically instable stem cells. Moreover, the findings point to an alternative pathway in intestinal carcinogenesis indicating that chromosomal instable stem cells can clonally expand contributing to epithelial regeneration at pre-tumorous stages in response to telomere dysfunction and p53 deletion.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 596.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009