PUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome

Cell Stem Cell. 2008 Jun 5;2(6):576-83. doi: 10.1016/j.stem.2008.03.009.


Radiation is one of the most effective cancer treatments. However, gastrointestinal (GI) syndrome is a major limiting factor in abdominal and pelvic radiotherapy. The loss of crypt stem cells or villus endothelial cells has been suggested to be responsible for radiation-induced intestinal damage. We report here a critical role of the BH3-only protein p53 upregulated modulator of apoptosis (PUMA) in the radiosensitivity of intestinal epithelium and pathogenesis of GI syndrome. PUMA was induced in a p53-dependent manner and mediated radiation-induced apoptosis via the mitochondrial pathway in the intestinal mucosa. PUMA-deficient mice exhibited blocked apoptosis in the intestinal progenitor and stem cells, enhanced crypt proliferation and regeneration, and prolonged survival following lethal doses of radiation. Unexpectedly, PUMA deficiency had little effect on radiation-induced intestinal endothelial apoptosis. Suppressing PUMA expression by antisense oligonucleotides provided significant intestinal radioprotection. Therefore, PUMA-mediated apoptosis in the progenitor and stem cell compartments is crucial for radiation-induced intestinal damage.

Publication types

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

MeSH terms

  • Adult Stem Cells / cytology
  • Adult Stem Cells / radiation effects*
  • Animals
  • Apoptosis / genetics
  • Apoptosis / radiation effects
  • Apoptosis Regulatory Proteins / biosynthesis
  • Apoptosis Regulatory Proteins / genetics*
  • Gastrointestinal Tract / cytology
  • Gastrointestinal Tract / radiation effects*
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / radiation effects
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / radiation effects
  • Mice
  • Neoplasms / radiotherapy
  • Oligonucleotides, Antisense
  • Radiation Injuries, Experimental / genetics*
  • Radiation Injuries, Experimental / pathology
  • Signal Transduction / radiation effects
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Protein p53 / radiation effects
  • Tumor Suppressor Proteins / biosynthesis
  • Tumor Suppressor Proteins / genetics*
  • Whole-Body Irradiation


  • Apoptosis Regulatory Proteins
  • Oligonucleotides, Antisense
  • PUMA protein, mouse
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins