SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress.
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.
Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, MD 20892, USA.
Hyun-Seok
HS
Kim
Krish
K
Patel
Kristi
K
Muldoon-Jacobs
Kheem S
KS
Bisht
Nukhet
N
Aykin-Burns
J Daniel
JD
Pennington
Riet
R
van der Meer
Phuongmai
P
Nguyen
Jason
J
Savage
Kjerstin M
KM
Owens
Athanassios
A
Vassilopoulos
Ozkan
O
Ozden
Seong-Hoon
SH
Park
Keshav K
KK
Singh
Sarki A
SA
Abdulkadir
Douglas R
DR
Spitz
Chu-Xia
CX
Deng
David
D
Gius
D000375:Aging / Q000502:physiology*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D056566:Sirtuin 3 / Q000235:genetics* / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism
C525046:Sirt3 protein, mouse; D013481:Superoxides; D056566:Sirtuin 3