Growth factors protect intestinal stem cells from radiation-induced apoptosis by suppressing PUMA through the PI3K/AKT/p53 axis
Open Access
- 7 December 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 29 (11), 1622-1632
- https://doi.org/10.1038/onc.2009.451
Abstract
Gastrointestinal toxicity is the primary limiting factor in abdominal and pelvic radiotherapy, but has no effective treatment currently. We recently showed a critical role of the BH3-only protein p53 upregulated modulator of apoptosis (PUMA) in acute radiation-induced GI damage and GI syndrome in mice. Growth factors such as insulin-like growth factor 1 (IGF-1) and basic fibroblast growth factor (bFGF) have been shown to protect against radiation-induced intestinal injury, although the underlying mechanisms remain to be identified. We report here the suppression of PUMA through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/p53 axis in the intestinal stem cells as a novel molecular mechanism of growth factor-mediated intestinal radioprotection. IGF-1 or bFGF impaired radiation-induced apoptosis and the expression of PUMA and p53 in the crypt cells and intestinal stem cells. Using colonic epithelial cells that undergo PUMA-dependent and radiation-induced apoptosis, we found that a PI3K inhibitor, dominant-negative PI3K or Mdm2 antagonist restored the induction of PUMA, p53 and apoptosis in the presence of growth factors. In contrast, overexpression of AKT suppressed the induction of PUMA and p53 by radiation. Furthermore, inhibiting PI3K or activating p53 abrogated growth factor-mediated suppression of apoptosis and PUMA expression in the intestinal crypts and stem cells after radiation.Keywords
This publication has 51 references indexed in Scilit:
- PUMA mediates EGFR tyrosine kinase inhibitor-induced apoptosis in head and neck cancer cellsOncogene, 2009
- Loss of p21Waf1/Cip1/Sdi1enhances intestinal stem cell survival following radiation injuryAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2009
- Small-Molecule Inhibitors of the MDM2-p53 Protein-Protein Interaction to Reactivate p53 Function: A Novel Approach for Cancer TherapyAnnual Review of Pharmacology and Toxicology, 2009
- Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformationNature, 2008
- PUMA, a potent killer with or without p53Oncogene, 2008
- Bmi1 is expressed in vivo in intestinal stem cellsNature Genetics, 2008
- Sp1 and p73 activate PUMA following serum starvationCarcinogenesis: Integrative Cancer Research, 2008
- Molecular properties of side population-sorted cells from mouse small intestineAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2008
- Identification of stem cells in small intestine and colon by marker gene Lgr5Nature, 2007
- Identification and classification of p53-regulated genesProceedings of the National Academy of Sciences of the United States of America, 1999