Pharmacological blockade of Bcl-2, Bcl-x(L) and Bcl-w by the BH3 mimetic ABT-737 has only minor impact on tumour development in p53-deficient mice
- Details
- Publication Year 2012-04,Volume 19,Issue #4,Page 623-632
- Journal Title
- CELL DEATH AND DIFFERENTIATION
- Publication Type
- Journal Article
- Abstract
- The tumour suppressor p53 transcriptionally regulates a range of target genes that control cell growth and survival. Mutations of p53 have been implicated in the development of similar to 50% of human cancers, including those instigated by exposure to mutagens. Although numerically rare, cancers can arise as a consequence of inherited mutations, such as in the Li-Fraumeni syndrome, which is caused by mutation of one p53 allele. Gene-targeted mice deficient for p53 have been generated to study this familial cancer syndrome. On a C57BL/6 background, p53-deficient mice develop primarily thymic lymphoma and more rarely sarcoma. Evasion of apoptosis is considered to be essential for neoplastic transformation. As proteins of the Bcl-2 family are the critical regulators of apoptosis, we investigated the role of the pro-survival members Bcl-2, Bcl-x(L) and Bcl-w in cancer development in p53(+/-) and p53(-/-) mice by testing whether ABT-737, a pharmacological inhibitor of these proteins, could prevent or delay tumourigenesis. Our studies showed that ABT-737 prophylaxis only caused a minor delay and reduction in gamma-radiation-induced thymic lymphoma development in p53(-/-) mice, but this was accompanied by a concomitant increase in sarcoma. These data show that, collectively, Bcl-2, Bcl-x(L) and Bcl-w have only minor roles in thymic lymphoma development elicited by defects in p53, and this may indicate that Mcl-1 and/or A1 may feature more prominently in this process. Cell Death and Differentiation (2012) 19, 623-632; doi:10.1038/cdd.2011.133; published online 14 October 2011
- Publisher
- NATURE PUBLISHING GROUP
- Keywords
- APOPTOTIC CELL-DEATH; LI-FRAUMENI-SYNDROME; BH3-ONLY PROTEINS; DNA-DAMAGE; FAMILY; P53; SURVIVAL; CANCER; INHIBITOR; BIM
- Research Division(s)
- Molecular Genetics Of Cancer; Stem Cells And Cancer
- Link To PubMed Central Version
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260394/
- Publisher's Version
- https://doi.org/10.1038/cdd.2011.133
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Creation Date: 2012-04-01 12:00:00