title: p53-insensitive PUMA down-regulation is essential in the early phase of liver regeneration after partial hepatectomy in mice.
abstract: OBJECTIVE
  Liver regeneration after partial hepatectomy involve proliferation and apoptosis of hepatocytes. PUMA, the well-known proapoptotic member of the Bcl-2 family, can respond to distinct stimuli. This study explores the role of PUMA and its relationship with other Bcl-2 family members in this process.
  
  
  METHODS
  The expression patterns of PUMA and its related proteins were investigated in livers after 70% hepatectomies. The contributions of PUMA to liver regeneration were assessed by manipulating its expression levels using adenovirus vectors. The differences in PUMA expression levels in human normal livers and hepatitis, as well as hepatoma tissues were characterised.
  
  
  RESULTS
  During the first 72h after hepatectomy, PUMA was highly down-regulated transcriptionally, while the levels of p53, Slug, Bax, and Bcl-X(L) proteins increased continuously. Highly induced expression of PUMA in the liver by Ad-PUMA caused lethal fulminant hepatitis 48h after treatment. Slightly induced expression was enough to impair liver regeneration, with an elevation of post-hepatectomy mortality, an increase of apoptosis, a decrease of proliferation, an up-regulation of Bax levels, an induction of inflammatory chemokines (KC and macrophage inflammatory protein-2), and an increase in the neutrophil infiltration relative to the control. In contrast to the results from the regenerating liver, PUMA expression showed an increased trend in human hepatitis and hepatoma tissues.
  
  
  CONCLUSIONS
  Sharply p53-insensitive down-regulation of PUMA, coupled with Bcl-X(L) up-regulation, may play a cytoprotective role in liver regeneration after hepatectomy. Furthermore, the increased expression of PUMA in hepatitis and hepatoma may indicate misregulation of the apoptotic network in these diseases.
authors.affiliation: Clinical Research Centre, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Song
authors.initials: S
authors.lastname: Chen
authors.forename: Jianming
authors.initials: J
authors.lastname: Zheng
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hao
authors.forename: Shengsheng
authors.initials: S
authors.lastname: Yang
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Wang
authors.forename: Huan
authors.initials: H
authors.lastname: Chen
authors.forename: Lizao
authors.initials: L
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Chaoqin
authors.initials: C
authors.lastname: Yu
authors.forename: Binghua
authors.initials: B
authors.lastname: Jiao
authors.forename: Zailong
authors.initials: Z
authors.lastname: Cai
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000503:physiopathology; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D006498:Hepatectomy / Q000379:methods* / Q000401:mortality; D006505:Hepatitis / Q000473:pathology / Q000503:physiopathology; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D006801:Humans; D008099:Liver / Q000473:pathology / Q000502:physiology / Q000601:surgery; D017114:Liver Failure, Acute / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein; D049452:Green Fluorescent Proteins