title: Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways.
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.
authors: 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.
authors: Zhiyang
authors: Z
authors: Chen
authors: Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou 310036, China.
authors: Weiwei
authors: W
authors: Yi
authors: Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena 07745, Germany.
authors: Yohei
authors: Y
authors: Morita
authors: Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou 310036, China.
authors: Hu
authors: H
authors: Wang
authors: Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou 310036, China.
authors: Yusheng
authors: Y
authors: Cong
authors: Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou 310036, China.
authors: Jun-Ping
authors: JP
authors: Liu
authors: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
authors: Zhicheng
authors: Z
authors: Xiao
authors: Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena 07745, Germany.
authors: K Lenhard
authors: KL
authors: Rudolph
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors: Tao
authors: T
authors: Cheng
authors: Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou 310036, China.
authors: Zhenyu
authors: Z
authors: Ju
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D003114:Colony-Forming Units Assay; D003517:Cyclopentanes / Q000494:pharmacology; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics*; D000071636:Protein Phosphatase 2C; D060888:Real-Time Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; C000591540:CCT007093; D003517:Cyclopentanes; D046912:Multiprotein Complexes; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C; D005472:Fluorouracil