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Cancer Cell. 2010 Jan 19;17(1):41-52. doi: 10.1016/j.ccr.2009.11.023.

SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress.

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  • 1Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, MD 20892, USA.

Abstract

The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3(-/-) mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3(-/-) MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3(-/-) MEFs and reverses the tumor-permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3(-/-) mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor.

Copyright (c) 2010 Elsevier Inc. All rights reserved.

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PMID:
20129246
[PubMed - indexed for MEDLINE]
PMCID:
PMC3711519
Free PMC Article

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