SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress

被引：677

作者：

Kim, Hyun-Seok ^{[1
]}

Patel, Krish ^{[2
]}

Muldoon-Jacobs, Kristi ^{[2
]}

Bisht, Kheem S. ^{[2
]}

Aykin-Burns, Nukhet ^{[3
]}

Pennington, J. Daniel ^{[2
]}

van der Meer, Riet ^{[4
]}

Nguyen, Phuongmai ^{[2
]}

Savage, Jason ^{[2
]}

Owens, Kjerstin M. ^{[6
]}

Vassilopoulos, Athanassios ^{[1
]}

Ozden, Ozkan ^{[2
]}

Park, Seong-Hoon ^{[2
]}

Singh, Keshav K. ^{[6
]}

Abdulkadir, Sarki A. ^{[4
]}

Spitz, Douglas R. ^{[3
]}

Deng, Chu-Xia ^{[1
]}

Gius, David ^{[2
,5
]}

机构：

[1] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA

[2] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[3] Univ Iowa, Dept Radiat Oncol, Free Rad & Radiat Biol Program, Iowa City, IA 52242 USA

[4] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Med Ctr, Dept Radiat Oncol, Nashville, TN 37232 USA

[6] Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA

来源：

CANCER CELL | 2010年 / 17卷 / 01期

基金：

美国国家卫生研究院;

关键词：

DNA-DAMAGE RESPONSE; HISTOLOGIC GRADE; CANCER; HOMOLOG; RAS; INSTABILITY; CHECKPOINT; PHYSIOLOGY; LONGEVITY; PATHWAYS;

D O I：

10.1016/j.ccr.2009.11.023

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：41 / 52

页数：12

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