Bmi1 regulates mitochondrial function and the DNA damage response pathway

被引：390

作者：

Liu, Jie ^{[1
]}

Cao, Liu ^{[1
,2
]}

Chen, Jichun

Song, Shiwei ^{[1
]}

Lee, In Hye ^{[1
]}

Quijano, Celia ^{[1
]}

Liu, Hongjun ^{[1
]}

Keyvanfar, Keyvan ^{[2
]}

Chen, Haoqian ^{[1
]}

Cao, Long-Yue ^{[1
]}

Ahn, Bong-Hyun ^{[1
]}

Kumar, Neil G. ^{[1
,3
]}

Rovira, Ilsa I. ^{[1
]}

Xu, Xiao-Ling ^{[4
]}

van Lohuizen, Maarten ^{[5
]}

Motoyama, Noboru ^{[6
]}

Deng, Chu-Xia ^{[4
]}

Finkel, Toren ^{[1
]}

机构：

[1] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA

[2] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA

[3] NIH, Howard Hughes Med Inst, Res Scholar Program, Bethesda, MD 20892 USA

[4] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA

[5] Netherlands Canc Inst, Div Mol Genet, NL-1066 CX Amsterdam, Netherlands

[6] Natl Ctr Geriatr & Gerontol, Natl Inst Longev Sci, Dept Geriatr Med, Aichi 4748522, Japan

来源：

NATURE | 2009年 / 459卷 / 7245期

关键词：

HEMATOPOIETIC STEM-CELLS; SELF-RENEWAL; REPAIR; PROLIFERATION; SENESCENCE; INK4A; MICE; P16(INK4A); TARGET; GROWTH;

D O I：

10.1038/nature08040

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：

Mice deficient in the Polycomb repressor Bmi1 develop numerous abnormalities including a severe defect in stem cell self-renewal, alterations in thymocyte maturation and a shortened lifespan. Previous work has implicated de-repression of the Ink4a/Arf (also known as Cdkn2a) locus as mediating many of the aspects of the Bmi1(-/-) phenotype. Here we demonstrate that cells derived from Bmi1(-/-) mice also have impaired mitochondrial function, a marked increase in the intracellular levels of reactive oxygen species and subsequent engagement of the DNA damage response pathway. Furthermore, many of the deficiencies normally observed in Bmi1(-/-) mice improve after either pharmacological treatment with the antioxidant N-acetylcysteine or genetic disruption of the DNA damage response pathway by Chk2 (also known as Chek2) deletion. These results demonstrate that Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis and indicate that the Polycomb family of proteins can coordinately regulate cellular metabolism with stem and progenitor cell function.

引用

页码：387 / U100

页数：7

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