Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways

被引：61

作者：

Chen, Zhiyang ^{[1
,2
]}

Yi, Weiwei ^{[1
]}

Morita, Yohei ^{[2
]}

Wang, Hu ^{[1
]}

Cong, Yusheng ^{[1
]}

Liu, Jun-Ping ^{[1
]}

Xiao, Zhicheng ^{[3
]}

Rudolph, K. Lenhard ^{[2
]}

Cheng, Tao ^{[4
,5
]}

Ju, Zhenyu ^{[1
]}

机构：

[1] Hangzhou Normal Univ, Sch Med, Inst Aging Res, Leibniz Link Partner Grp Stem Cell Aging, Hangzhou 310036, Zhejiang, Peoples R China

[2] Fritz Lipmann Inst, Leibniz Inst Age Res, D-07745 Jena, Germany

[3] Monash Univ, Dept Anat & Dev Biol, Clayton, Vic 3800, Australia

[4] Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin 300020, Peoples R China

[5] Peking Union Med Coll, Tianjin 300020, Peoples R China

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

中国国家自然科学基金;

关键词：

DNA-DAMAGE RESPONSE; PHOSPHATASE WIP1; SELF-RENEWAL; MICE; QUIESCENCE; DEFECTS; DIFFERENTIATION; HETEROGENEITY; TUMORIGENESIS; COMPARTMENT;

D O I：

10.1038/ncomms7808

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：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Wild-type p53-induced phosphatase 1 (Wip1) negatively regulates several tumour suppressor and DNA damage response pathways. However, the impact of Wip1 on haematopoietic stem cell (HSC) homeostasis and aging remains unknown. Here we show that Wip1 is highly expressed in HSCs but decreases with age. Wip1-deficient (Wip1(-/-)) mice exhibited multifaceted HSC aging phenotypes, including the increased pool size and impaired repopulating activity. Deletion of p53 rescued the multilineage repopulation defect of Wip1(-/-) HSCs without affecting cellular senescence or apoptosis, indicating that the Wip1-p53 axis regulates HSC differentiation in a manner independent of conventional p53 pathways. However, p53 deletion did not influence the increased HSC pool size in Wip1(-/-) mice. Interestingly, the expansion of HSCs in Wip1(-/-) mice was due to an mTORC1-mediated HSC proliferation. Thus, our study reveals a mechanism of stem cell aging, in which distinct effects of p53 and mTORC1 pathways on HSC aging are governed by Wip1.

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页数：11

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[1]

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mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells [J].

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[7]

Hematopoietic stem cell quiescence maintained by p21cip1/waf1 [J].

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Shen, HM ;

Yang, YG ;

Dombkowski, D ;

Sykes, M ;

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[10]

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