期刊
GENES & DEVELOPMENT
卷 24, 期 15, 页码 1608-1613出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1940110
关键词
Apoptosis; DNA damage; p53; Puma; Noxa; tumor suppressor
资金
- NHMRC [257502, CDA 406675, CDA 461274, 461214]
- Leukemia and Lymphoma Society [7015]
- NIH [CA043540]
- JDRF/NHMRC
- Cancer Council Victoria
Although tumor development requires impaired apoptosis, we describe a novel paradigm of apoptosis-dependent tumorigenesis. Because DNA damage triggers apoptosis through p53-mediated induction of BH3-only proteins Puma and Noxa, we explored their roles in gamma-radiation-induced thymic lymphomagenesis. Surprisingly, whereas Noxa loss accelerated it, Puma loss ablated tumorigenesis. Tumor suppression by Puma deficiency reflected its protection of leukocytes from gamma-irradiation-induced death, because their glucocorticoid-mediated decimation in Puma-deficient mice activated cycling of stem/progenitor cells and restored thymic lymphomagenesis. Our demonstration that cycles of cell attrition and repopulation by stem/progenitor cells can drive tumorigenesis has parallels in human cancers, such as therapy-induced malignancies.
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