p53-Mediated Stress and Tissue-Dependent Cell Fate Decisions; Implications for p53 Targeting

Abstract SCI-3

The activity of the p53 tumor suppressor is tightly regulated by Mdm2, an E3 ubiquitin ligase that targets p53 for degradation. Loss of Mdm2 in embryos or in individual tissues in vivo results in cell lethal events that are p53-dependent. A hypomorphic allele of p53, p53515C (encoding the p53R172P protein), rescues the embryonic lethality of Mdm2–/– mice. Mdm2–/– p53515C/515C mice, however, die by postnatal day 13 due to hematopoietic failure. In these mice, hematopoiesis is normal during embryogenesis. After birth, these mice had elevated reactive oxygen species (ROS), which activated p53R172P. p53R172P, in turn, induced ROS, creating a loop that caused cell death in the hematopoietic compartment. This phenotype was partially rescued with antioxidant treatment. The cell cycle inhibitor, p16, was also stabilized due to ROS, and its loss increased cell cycling and partially rescued hematopoiesis and survival. Thus, Mdm2 is required to control ROS-induced p53 levels for sustainable hematopoiesis.