PUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome.
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.
Department of Pathology, University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.
Wei
W
Qiu
Eleanor B
EB
Carson-Walter
Hongtao
H
Liu
Michael
M
Epperly
Joel S
JS
Greenberger
Gerard P
GP
Zambetti
Lin
L
Zhang
Jian
J
Yu
D053687:Adult Stem Cells / Q000166:cytology / Q000528:radiation effects*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics*; D041981:Gastrointestinal Tract / Q000166:cytology / Q000528:radiation effects*; D005786:Gene Expression Regulation / Q000235:genetics / Q000528:radiation effects; D007413:Intestinal Mucosa / Q000166:cytology / Q000528:radiation effects; D051379:Mice; D009369:Neoplasms / Q000532:radiotherapy; D016376:Oligonucleotides, Antisense; D011833:Radiation Injuries, Experimental / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D014916:Whole-Body Irradiation
D051017:Apoptosis Regulatory Proteins; D016376:Oligonucleotides, Antisense; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins