PMID- 25704606 OWN - NLM STAT- MEDLINE DCOM- 20150804 LR - 20211203 IS - 1527-3350 (Electronic) IS - 0270-9139 (Linking) VI - 61 IP - 6 DP - 2015 Jun TI - Inhibition of wild-type p53-induced phosphatase 1 promotes liver regeneration in mice by direct activation of mammalian target of rapamycin. PG - 2030-41 LID - 10.1002/hep.27755 [doi] AB - 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. CONCLUSION: 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. CI - (c) 2015 by the American Association for the Study of Liver Diseases. FAU - Zhang, Lingling AU - Zhang L AD - Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, School of Medicine, Hangzhou Normal University, Hangzhou, China. FAU - Liu, Leiming AU - Liu L AD - Sir Runrun Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China. FAU - He, Zhiyong AU - He Z AD - The Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China. FAU - Li, Guangbing AU - Li G AD - Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. FAU - Liu, Junping AU - Liu J AD - Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, School of Medicine, Hangzhou Normal University, Hangzhou, China. FAU - Song, Zhangfa AU - Song Z AD - Sir Runrun Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China. FAU - Jin, Hongchuan AU - Jin H AD - Sir Runrun Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China. FAU - Rudolph, Karl Lenhard AU - Rudolph KL AD - Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena, Germany. FAU - Yang, Huayu AU - Yang H AD - Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. FAU - Mao, Yilei AU - Mao Y AD - Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. FAU - Zhang, Lianfeng AU - Zhang L AD - Institute of Laboratory Animal Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. FAU - Zhang, Hongbing AU - Zhang H AD - Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. FAU - Xiao, Zhicheng AU - Xiao Z AD - The Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China. FAU - Ju, Zhenyu AU - Ju Z AD - Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, School of Medicine, Hangzhou Normal University, Hangzhou, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150325 PL - United States TA - Hepatology JT - Hepatology (Baltimore, Md.) JID - 8302946 RN - 0 (Cyclin-Dependent Kinase Inhibitor p21) RN - 0 (Multiprotein Complexes) RN - 0 (NF-kappa B) RN - 0 (Tumor Suppressor Protein p53) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.1.3.16 (Phosphoprotein Phosphatases) RN - EC 3.1.3.16 (Ppm1d protein, mouse) RN - EC 3.1.3.16 (Protein Phosphatase 2C) SB - IM MH - Animals MH - Cell Proliferation MH - Cells, Cultured MH - Cyclin-Dependent Kinase Inhibitor p21/metabolism MH - Hepatectomy MH - Hepatocytes/*physiology MH - *Liver Regeneration MH - MAP Kinase Signaling System MH - Mechanistic Target of Rapamycin Complex 1 MH - Mice MH - Multiprotein Complexes/metabolism MH - NF-kappa B/metabolism MH - Phosphoprotein Phosphatases/*metabolism MH - Protein Phosphatase 2C MH - TOR Serine-Threonine Kinases/*metabolism MH - Tumor Suppressor Protein p53/metabolism EDAT- 2015/02/24 06:00 MHDA- 2015/08/05 06:00 CRDT- 2015/02/24 06:00 PHST- 2014/10/02 00:00 [received] PHST- 2015/02/14 00:00 [accepted] PHST- 2015/02/24 06:00 [entrez] PHST- 2015/02/24 06:00 [pubmed] PHST- 2015/08/05 06:00 [medline] AID - 10.1002/hep.27755 [doi] PST - ppublish SO - Hepatology. 2015 Jun;61(6):2030-41. doi: 10.1002/hep.27755. Epub 2015 Mar 25.