Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, MD 20892, USA.
Cancer Cell. 2010 Jan 19;17(1):41-52. doi: 10.1016/j.ccr.2009.11.023.
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.
Sirtuin 基因家族（SIRT）被假设可以调节衰老过程并在细胞修复中发挥作用。这项工作表明，SIRT3（-/-）小鼠胚胎成纤维细胞（MEF）表现出异常的线粒体生理学，以及应激诱导的超氧化物水平增加和基因组不稳定性。在 SIRT3（-/-）MEF 中表达单个致癌基因（Myc 或 Ras）会导致体外转化和细胞内代谢的改变。超氧化物歧化酶可防止 SIRT3（-/-）MEF 中单个致癌基因的转化，并逆转肿瘤允许表型以及应激诱导的基因组不稳定性。此外，SIRT3（-/-）小鼠会发展出 ER/PR 阳性的乳腺肿瘤。最后，人类乳腺和其他人类癌症标本显示 SIRT3 水平降低。这些结果表明 SIRT3 是一种具有基因组表达和线粒体定位的肿瘤抑制因子。
