Der Verlust von p53 verhindert das Entfernen von chromosomal-intestinalen Stammzellen in Mäusen mit dysfunktionellen Telomeren
FacultiesFakultät für Naturwissenschaften
LicenseStandard (Fassung vom 01.10.2008)
Deletion of components of the DNA-damage signaling pathway can rescue the maintenance and the function of stem cells in aging telomere dysfunctional mice (Choudhury et al; Schätzlein et al.). p53 is activated in response to DNA damage leading to induction of apoptosis or p21-dependent cell cycle arrest. Depletion of intestinal stem cells and crypt atrophy represent major phenotypes in aging telomere dysfunctional mice. To analyze the in vivo role of p53 in this context, Terc-/- mice were crossed to conditional, intestine-specific Trp53-knock out mice. In aging IF1 Terc+/- Trp53 deletion did not induce an obvious intestinal phenotype until 18 months. In contrast Trp53 deletion significantly shortened the lifespan of iG4 Terc-/- Trp53-/- animals compared to iG4 Terc-/- Trp53+/+. This reduction correlated with earlier appearance of crypt atrophy and weight loss but was not associated with tumor formation. Deletion of the Trp53 gene resulted in complete abrogation of p21 activation, accumulation of DNA damage and an increase in apoptosis in the intestinal epithelium of these mice. Moreover this correlated with an accumulation of intestinal stem cells carrying high levels of DNA damage. Our results provide first experimental evidence that p53 induction has a protective role preventing accumulation of damaged stem cells and organ degeneration induced in aging in the context of telomere dysfunction.
Subject HeadingsProtein p53 [GND]
Protein P53 [GND]
Telomer <Molekulargenetik> [GND]
Chromosomal instability [MeSH]