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

Zhiyang Chen; Weiwei Yi; Yohei Morita; Hu Wang; Yusheng Cong; Jun-Ping Liu; Zhicheng Xiao; K Lenhard Rudolph; Tao Cheng; Zhenyu Ju

doi:10.1038/ncomms7808

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

Nat Commun. 2015 Apr 16:6:6808. doi: 10.1038/ncomms7808.

Authors

Affiliations

¹ 1] Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou 310036, China [2] Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena 07745, Germany.
² Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou 310036, China.
³ Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena 07745, Germany.
⁴ Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
⁵ State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.

PMID: 25879755
DOI: 10.1038/ncomms7808

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antimetabolites, Antineoplastic / pharmacology
Apoptosis / drug effects
Apoptosis / genetics
Blotting, Western
Bone Marrow Cells
Bone Marrow Transplantation
Cell Cycle / drug effects
Cell Cycle / genetics
Cellular Senescence / drug effects
Cellular Senescence / genetics*
Colony-Forming Units Assay
Cyclopentanes / pharmacology
Flow Cytometry
Fluorouracil / pharmacology
Hematopoietic Stem Cells / cytology*
Hematopoietic Stem Cells / drug effects
Hematopoietic Stem Cells / metabolism
Homeostasis
Mechanistic Target of Rapamycin Complex 1
Mice
Mice, Knockout
Multiprotein Complexes / genetics*
Multiprotein Complexes / metabolism
Phosphoprotein Phosphatases / antagonists & inhibitors
Phosphoprotein Phosphatases / genetics*
Protein Phosphatase 2C
Real-Time Polymerase Chain Reaction
TOR Serine-Threonine Kinases / genetics*
TOR Serine-Threonine Kinases / metabolism
Thiophenes / pharmacology
Tumor Suppressor Protein p53 / genetics*
Tumor Suppressor Protein p53 / metabolism

Substances

Antimetabolites, Antineoplastic
CCT007093
Cyclopentanes
Multiprotein Complexes
Thiophenes
Tumor Suppressor Protein p53
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
Phosphoprotein Phosphatases
Ppm1d protein, mouse
Protein Phosphatase 2C
Fluorouracil