title: Inhibition of wild-type p53-induced phosphatase 1 promotes liver regeneration in mice by direct activation of mammalian target of rapamycin.
abstract: The liver possesses extraordinary regenerative capacity in response to injury. However, liver regeneration (LR) is often impaired in disease conditions. Wild-type p53-induced phosphatase 1 (Wip1) is known as a tumor promoter and enhances cell proliferation, mainly by deactivating antioncogenes. However, in this work, we identified an unexpected role of Wip1 in LR. In contrast to its known role in promoting cell proliferation in extrahepatic tissue, we found that Wip1 suppressed hepatocyte proliferation after partial hepatectomy (PHx). Deletion of Wip1 increased the rate of LR after PHx. Enhanced LR in Wip1-deficient mice was a result of the activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway. Furthermore, we showed that Wip1 physically interacted with and dephosphorylated mTOR. Interestingly, inhibition of Wip1 also activated the p53 pathway during LR. Disruption of the p53 pathway further enhanced LR in Wip1-deficient mice. Therefore, inhibition of Wip1 has a dual role in LR, i.e., promoting hepatocyte proliferation through activation of the mTORC1 pathway, meanwhile suppressing LR through activation of the p53 pathway. However, the proregenerative role of mTORC1 overwhelms the antiproliferative role of p53. Furthermore, CCT007093, a Wip1 inhibitor, enhanced LR and increased the survival rate of mice after major hepatectomy.
  
  
  CONCLUSIONS
  mTOR is a new direct target of Wip1. Wip1 inhibition can activate the mTORC1 pathway and enhance hepatocyte proliferation after hepatectomy. These findings have clinical applications in cases where LR is critical, including acute liver failure, cirrhosis, or small-for-size liver transplantations.
authors.affiliation: Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, School of Medicine, Hangzhou Normal University, Hangzhou, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Sir Runrun Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Leiming
authors.initials: L
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: He
authors.affiliation: Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Guangbing
authors.initials: G
authors.lastname: Li
authors.affiliation: Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, School of Medicine, Hangzhou Normal University, Hangzhou, China.
authors.forename: Junping
authors.initials: J
authors.lastname: Liu
authors.affiliation: Sir Runrun Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Zhangfa
authors.initials: Z
authors.lastname: Song
authors.affiliation: Sir Runrun Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Hongchuan
authors.initials: H
authors.lastname: Jin
authors.affiliation: Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena, Germany.
authors.forename: Karl Lenhard
authors.initials: KL
authors.lastname: Rudolph
authors.affiliation: Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Huayu
authors.initials: H
authors.lastname: Yang
authors.affiliation: Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Yilei
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Institute of Laboratory Animal Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, School of Medicine, Hangzhou Normal University, Hangzhou, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006498:Hepatectomy; D022781:Hepatocytes / Q000502:physiology*; D008115:Liver Regeneration; D020935:MAP Kinase Signaling System; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D046912:Multiprotein Complexes; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C