1. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress.
- Author
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Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, van der Meer R, Nguyen P, Savage J, Owens KM, Vassilopoulos A, Ozden O, Park SH, Singh KK, Abdulkadir SA, Spitz DR, Deng CX, and Gius D
- Subjects
- Animals, Breast Neoplasms genetics, Breast Neoplasms metabolism, Female, Fibroblasts metabolism, Humans, Immunohistochemistry, Mice, Mice, Knockout, Oxidative Stress physiology, Sirtuin 3 metabolism, Superoxides metabolism, Aging physiology, Cell Transformation, Neoplastic genetics, Genes, Tumor Suppressor, Mitochondria metabolism, Sirtuin 3 genetics, Stress, Physiological physiology
- 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.)
- Published
- 2010
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