title: PP2Acα positively regulates the termination of liver regeneration in mice through the AKT/GSK3β/Cyclin D1 pathway.
abstract: OBJECTIVE
  Liver injury triggers a highly organized and ordered liver regeneration (LR) process. Once regeneration is complete, a stop signal ensures that the regenerated liver is an appropriate functional size. The inhibitors and stop signals that regulate LR are unknown, and only limited information is available about these mechanisms.
  
  
  METHODS
  A 70% partial hepatectomy (PH) was performed in hepatocyte-specific PP2Acα-deleted (PP2Acα(-/-)) and control (PP2Acα(+/+)) mice. LR was estimated by liver weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were analyzed.
  
  
  RESULTS
  We found that the catalytic subunit of PP2A was markedly upregulated during the late stage of LR. PP2Acα(-/-) mice showed prolonged LR termination, an increased liver size compared to the original mass and lower levels of serum ALT and AST compared with control mice. In these mice, cyclin D1 protein levels, but not mRNA levels, were increased. Mechanistically, AKT activated by the loss of PP2Acα inhibited glycogen synthase kinase 3β (GSK3β) activity, which led to the accumulation of cyclin D1 protein and accelerated hepatocyte proliferation at the termination stage. Treatment with the PI3K inhibitor wortmannin at the termination stage was sufficient to inhibit cyclin D1 accumulation and hepatocyte proliferation.
  
  
  CONCLUSIONS
  PP2Acα plays an essential role in the proper termination of LR via the AKT/GSK3β/Cyclin D1 pathway. Our findings enrich the understanding of the molecular mechanism that controls the termination of LR and provides a potential therapeutic target for treating liver injury.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Lai
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Zhao
authors.affiliation: Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Institute of Chinese Medicine, Nanjing 210028, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Ou-Yang
authors.initials: OY
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China; Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210093, China.
authors.forename: Wei-Bo
authors.initials: WB
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: En-Ze
authors.initials: EZ
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Zi-Han
authors.initials: ZH
authors.lastname: Yu
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Gina
authors.initials: G
authors.lastname: Lee
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210093, China.
authors.forename: De-Cai
authors.initials: DC
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Min-Sheng
authors.initials: MS
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China. Electronic address: gaoxiang@nju.edu.cn.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China. Electronic address: licj@nju.edu.cn.
authors.forename: Chao-Jun
authors.initials: CJ
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, Nanjing University, Nanjing 210093, China. Electronic address: xuebin@nju.edu.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D019938:Cyclin D1 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019938:Cyclin D1; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2
keywords: AKT; GSK3β; Liver injury; PP2A; Termination of liver regeneration