title: Loss of Gsα impairs liver regeneration through a defect in the crosstalk between cAMP and growth factor signaling.
abstract: OBJECTIVE
  The stimulatory G protein α subunit (Gsα) activates the cAMP-dependent pathway by stimulating the production of cAMP and participates in diverse cell processes. Aberrant expression of Gsα results in various pathophysiological disorders, including tumorigenesis, but little is known about its role in liver regeneration.
  
  
  METHODS
  We generated a hepatocyte-specific Gsα gene knockout mouse to demonstrate the essential role of Gsα in liver regeneration using a mouse model with 70% partial hepatectomy (PH) or an intraperitoneal injection of carbon tetrachloride (CCl4).
  
  
  RESULTS
  Gsα inactivation dramatically impaired liver regeneration and blocked proliferating hepatocytes in G1/S transition due to the simultaneous depression of cyclin-dependent kinase 2 (CDK2) and cyclin E1. Loss of Gsα led to a fundamental alteration in gene profiles. Among the altered signaling cascades, the MAPK/Erk pathway, which is downstream of growth factor signaling, was disrupted secondary to a defect in phosphorylated Raf1 (pRaf1), resulting in a deficiency in phosphorylated CREB (pCREB) and CDK2 ablation. The lack of pRaf1 also resulted in a failure to phosphorylate retinoblastoma, which releases and activates E2F1, and a decrease in cyclin E1. Although these factors could be phosphorylated through both Gsα and growth factor signaling, the unique function of Raf1 in the growth factor cascade collapsed in response to the lack of Gsα.
  
  
  CONCLUSIONS
  The growth factor signaling pathway that promotes hepatocyte proliferation is dependent on Gsα signaling. Loss of Gsα leads to a breakdown of the crosstalk between cAMP and growth factor signaling and dramatically impairs liver regeneration.
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China; Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Changli
authors.initials: C
authors.lastname: Lu
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xia
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China; Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, China.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Xufeng
authors.initials: X
authors.lastname: Lu
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China; Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, China.
authors.forename: Maling
authors.initials: M
authors.lastname: Gou
authors.affiliation: Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China; Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Ji
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China; Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, China.
authors.forename: Keting
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Laboratory of Cell and Gene Therapy, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yu
authors.affiliation: Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China; Department of Pathology, West China Hospital, Sichuan University, Chengdu, China. Electronic address: hongbu@scu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Bu
authors.affiliation: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China; Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, China. Electronic address: shiyujun@scu.edu.cn.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism; D018816:Genes, cdc / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D000242:Cyclic AMP; D051357:Cyclin-Dependent Kinase 2; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: CDK2; Cyclin E; G1/S transition; MAPK/Erk; Rb/E2F1