Apoptosis-promoted tumorigenesis: gamma-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death
- Author(s)
- Michalak, EM; Vandenberg, CJ; Delbridge, ARD; Wu, L; Scott, CL; Adams, JM; Strasser, A;
- Details
- Publication Year 2010-08-01,Volume 24,Issue #15,Page 1608-1613
- Journal Title
- GENES & DEVELOPMENT
- Publication Type
- Journal Article
- Abstract
- 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.
- Publisher
- COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
- Keywords
- PROTECTS HEMATOPOIETIC STEM; BH3-ONLY PROTEINS PUMA; PROAPOPTOTIC GENE; TRANSGENIC MICE; CANCER-CELLS; BCL-2 FAMILY; P53; RADIATION; DELETION; THERAPY
- Publisher's Version
- https://doi.org/10.1101/gad.1940110
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2010-08-01 12:00:00