Thep53 pathway in the homeostasis of the intestinal epithelium.

摘要

The p53 tumor suppressor is critical to inhibit tumorigenesis by inducing cell cycle arrest or apoptosis in damaged cells. p53 is regulated by two major inhibitors, Mdm2 and Mdm4. Mice with loss of Mdm2 or Mdm4 are lethal due to increased p53 activity. Additionally, the use of conditional alleles has uncovered the importance of these inhibitors in the Central Nervous System and in cardiomyocytes. Importantly, the roles that Mdm2 and Mdm4 play in tissues with high turnover capacity such as the small intestine, where p53 has a critical function after DNA damage, are unknown. To this end, we have engineered mice with loss of Mdm2 or Mdm4 in the intestinal epithelium. Surprisingly, loss of Mdm2 (Mdm2 intDelta) in this tissue yields viable animals. However, Mdm2intDelta neonates display multiple intestinal abnormalities such as hyperplasia and hypertrophy in the intervillus pockets, villus atrophy, enterocyte vacuolization, and inflammation. These defects correlate with a drastic increase in p53-dependent apoptosis in both highly proliferative and differentiated cell compartments of this tissue. Unexpectedly, the observed phenotypes disappear with age due to the ability of the tissue to compensate for p53-mediated cellular loss. The tissue selects against cells that have lost the Mdm2 allele and increases its proliferation capacity. Enhancement of proliferation is achieved at least in part by the activation of the Wnt canonical pathway. Additionally, the intestinal stem cell population is enriched and presumably leads to an increase in crypt multiplication, which is essential for tissue growth. On the other hand, mice with Mdm4 deficiency (Mdm2intDelta) in the intestinal epithelium are also viable but display a less severe intestinal phenotype than Mdm2intDelta mice. In contrast to Mdm2intDelta mice, Mdm2 intDelta mice show an increase in p53-dependent apoptosis exclusively in the highly proliferative compartment of the intestine and do not exhibit alterations in cellular proliferation. Together, these data indicate that Mdm2 and Mdm4 regulate p53 differentially in the intestinal epithelium. While Mdm2 modulates p53 function in both, highly proliferative and differentiated compartments of the small intestine, Mdm4 controls p53 activity exclusively in the proliferative compartment of this tissue. Importantly, this study has led to our understanding of how highly proliferative tissues such as the intestinal epithelium respond to p53 activation to promote organismal survival.