RRM2B Suppresses Activation of the Oxidative Stress Pathway and is Up-regulated by P53 During Senescence

被引:28
|
作者
Kuo, Mei-Ling [1 ]
Sy, Alexander J. [1 ]
Xue, Lijun [1 ]
Chi, Martin [1 ]
Lee, Michelle T. -C. [1 ]
Yen, Terence [1 ]
Chiang, Mei-Iok [1 ]
Chang, Lufen [1 ]
Chu, Peiguo [3 ]
Yen, Yun [1 ,2 ]
机构
[1] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Pharmacol, Duarte, CA 91010 USA
[2] Taipei Med Univ, Taipei 110, Taiwan
[3] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA
来源
SCIENTIFIC REPORTS | 2012年 / 2卷
关键词
MAMMALIAN RIBONUCLEOTIDE REDUCTASE; ONCOGENE-INDUCED SENESCENCE; RENAL-FAILURE; DNA-DAMAGE; PROTEIN; CELLS; PROSTATE; ARREST; KINASE; TARGET;
D O I
10.1038/srep00822
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
RRM2B is the DNA damage-inducible small subunit of ribonucleotide reductase, the rate-limiting enzyme in de novo deoxyribonucleoside triphosphate synthesis. Although RRM2B is implicated in DNA repair and the maintenance of mitochondrial DNA content, the regulation and function of RRM2B in senescence have not been previously established. Here, we show that RRM2B is highly induced in a p53-dependent manner during senescence in primary human fibroblast IMR90 cells and is expressed at higher levels in senescent precancerous human prostatic intraepithelial neoplasm lesions compared to adjacent normal prostate glands. Paradoxically, silencing RRM2B expression leads to an increase in the level of reactive oxygen species, mitochondrial membrane depolarization, and premature senescence in a p38MAPK- and p53-dependent manner in young fibroblasts. Consistently, induction of senescence is accelerated in Rrm2b deficient mouse embryo fibroblasts. Our data demonstrate that RRM2B is induced by stress signals prior to the onset of senescence and prevents premature oxidative stress-induced senescence.
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页数:9
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