Uncoupling p53 Functions in Radiation-Induced Intestinal Damage via PUMA and p21

Mol Cancer Res. 2011 May;9(5):616-25. doi: 10.1158/1541-7786.MCR-11-0052. Epub 2011 Mar 30.

Abstract

The role of p53 in tissue protection is not well understood. Loss of p53 blocks apoptosis in the intestinal crypts following irradiation but paradoxically accelerates gastrointestinal (GI) damage and death. PUMA and p21 are the major mediators of p53-dependent apoptosis and cell-cycle checkpoints, respectively. To better understand these two arms of p53 response in radiation-induced GI damage, we compared animal survival, as well as apoptosis, proliferation, cell-cycle progression, DNA damage, and regeneration in the crypts of WT, p53 knockout (KO), PUMA KO, p21 KO, and p21/PUMA double KO (DKO) mice in a whole body irradiation model. Deficiency in p53 or p21 led to shortened survival but accelerated crypt regeneration associated with massive nonapoptotic cell death. Nonapoptotic cell death is characterized by aberrant cell-cycle progression, persistent DNA damage, rampant replication stress, and genome instability. PUMA deficiency alone enhanced survival and crypt regeneration by blocking apoptosis but failed to rescue delayed nonapoptotic crypt death or shortened survival in p21 KO mice. These studies help to better understand p53 functions in tissue injury and regeneration and to potentially improve strategies to protect or mitigate intestinal damage induced by radiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / radiation effects*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Caspases / metabolism
  • Caspases / radiation effects
  • Cell Cycle / radiation effects
  • Cell Death / radiation effects
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • DNA Damage / radiation effects
  • DNA Replication / radiation effects
  • Histones / metabolism
  • Histones / radiation effects
  • Intestinal Diseases / genetics*
  • Intestinal Diseases / metabolism
  • Intestines / pathology
  • Intestines / radiation effects*
  • Mice
  • Mice, Knockout
  • Radiation Injuries / genetics*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Whole-Body Irradiation

Substances

  • Apoptosis Regulatory Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Histones
  • Tumor Suppressor Protein p53
  • gamma-H2AX protein, mouse
  • Caspases