Ribonucleotide reductase subunit p53R2 regulates mitochondria homeostasis and function in KB and PC-3 cancer cells

被引:15
|
作者
Wang, Xiaochen [1 ,2 ]
Liu, Xiyong [1 ]
Xue, Lijun [1 ]
Zhang, Keqiang [3 ]
Kuo, Mei-Ling [1 ]
Hu, Shuya [1 ]
Zhou, Bingsen [1 ]
Ann, David [1 ]
Zhang, Suzhan [2 ]
Yen, Yun [1 ]
机构
[1] City Hope Comprehens Canc Ctr, Beckman Res Inst, Dept Mol Pharmacol, Duarte, CA 91010 USA
[2] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Surg Oncol, Hangzhou 310009, Zhejiang, Peoples R China
[3] City Hope Comprehens Canc Ctr, Beckman Res Inst, Translat Res Core Lab, Duarte, CA 91010 USA
关键词
p53R2 (RRM2B); Mitochondrial DNA (mtDNA) synthesis; ATP synthesis; Membrane potential; Cytochrome c oxidase; DNA-DAMAGE; RESTING CELLS; DNTP POOLS; IN-VITRO; PROTEIN; MUTATIONS; DEPLETION; TRIPHOSPHATE; MICE;
D O I
10.1016/j.bbrc.2011.05.114
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Ribonucleotide reductase (RR) is a rate-limiting enzyme that catalyzes de novo conversion of ribonucleotide 5'-diphosphates to the corresponding 2'-deoxynucleotide, essential for DNA synthesis and replication. The mutations or knockout of RR small subunit, p53R2, results in the depletion of mitochondria! DNA (mtDNA) in human, implying that p53R2 might play a critical role for maintaining mitochondria] homeostasis. In this study, siRNA against p53R2 knockdown approach is utilized to examine the impact of p53R2 depletion on mitochondria and to derive underlying mechanism in KB and PC-3 cancer cells. Our results reveal that the p53R2 expression not only positively correlates with mtDNA content, but also partakes in the proper mitochondria function, such as ATP synthesis, cytochrome c oxidase activity and membrane potential maintenance. Furthermore, overexpression of p53R2 reduces intracellular ROS and protects the mitochondrial membrane potential against oxidative stress. Unexpectedly, knockdown of p53R2 has a modest, if any, effect on mitochondrial and total cellular dNTP pools. Taken together, our study provides functional evidence that mitochondria is one of p53R2-targeted organelles and suggests an unexpected function of p53R2, which is beyond known RR function on dNTP synthesis, in mitochondrial homeostatic control. (C) 2011 Elsevier Inc. All rights reserved.
引用
收藏
页码:102 / 107
页数:6
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