Your browser doesn't support javascript.
loading
JCAD deficiency delayed liver regenerative repair through the Hippo-YAP signalling pathway.
Zhang, Li; Yang, Yong-Yu; Xie, Li; Zhou, Yuan; Zhong, Zhenxing; Ding, Jia; Wang, Zhong-Hua; Wang, Yu-Li; Liu, Xiu-Ping; Yu, Fa-Xing; Wu, Jian.
Afiliação
  • Zhang L; Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China.
  • Yang YY; Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China.
  • Xie L; Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China.
  • Zhou Y; Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China.
  • Zhong Z; Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University Shanghai Medical College, Shanghai, China.
  • Ding J; Jing'an Central District Hospital, Shanghai, China.
  • Wang ZH; Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China.
  • Wang YL; Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China.
  • Liu XP; Department of Pathology and Laboratory Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • Yu FX; Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University Shanghai Medical College, Shanghai, China.
  • Wu J; Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, China.
Clin Transl Med ; 14(3): e1630, 2024 03.
Article em En | MEDLINE | ID: mdl-38509842
ABSTRACT
BACKGROUND AND

AIMS:

Liver regeneration retardation post partial hepatectomy (PH) is a common clinical problem after liver transplantation. Identification of key regulators in liver regeneration post PH may be beneficial for clinically improving the prognosis of patients after liver transplantation. This study aimed to clarify the function of junctional protein-associated with coronary artery disease (JCAD) in liver regeneration post PH and to reveal the underlying mechanisms.

METHODS:

JCAD knockout (JCAD-KO), liver-specific JCAD-KO (Jcad△Hep) mice and their control group were subjected to 70% PH. RNA sequencing was conducted to unravel the related signalling pathways. Primary hepatocytes from KO mice were treated with epidermal growth factor (EGF) to evaluate DNA replication. Fluorescent ubiquitination-based cell cycle indicator (FUCCI) live-imaging system was used to visualise the phases of cell cycle.

RESULTS:

Both global and liver-specific JCAD deficiency postponed liver regeneration after PH as indicated by reduced gene expression of cell cycle transition and DNA replication. Prolonged retention in G1 phase and failure to transition over the cell cycle checkpoint in JCAD-KO cell line was indicated by a FUCCI live-imaging system as well as pharmacologic blockage. JCAD replenishment by adenovirus reversed the impaired DNA synthesis in JCAD-KO primary hepatocyte in exposure to EGF, which was abrogated by a Yes-associated protein (YAP) inhibitor, verteporfin. Mechanistically, JCAD competed with large tumour suppressor 2 (LATS2) for WWC1 interaction, leading to LATS2 inhibition and thereafter YAP activation, and enhanced expression of cell cycle-associated genes.

CONCLUSION:

JCAD deficiency led to delayed regeneration after PH as a result of blockage in cell cycle progression through the Hippo-YAP signalling pathway. These findings uncovered novel functions of JCAD and suggested a potential strategy for improving graft growth and function post liver transplantation. KEY POINTS JCAD deficiency leads to an impaired liver growth after PH due to cell division blockage. JCAD competes with LATS2 for WWC1 interaction, resulting in LATS2 inhibition, YAP activation and enhanced expression of cell cycle-associated genes. Delineation of JCADHippoYAP signalling pathway would facilitate to improve prognosis of acute liver failure and graft growth in living-donor liver transplantation.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Moléculas de Adesão Celular / Transplante de Fígado / Regeneração Hepática Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Moléculas de Adesão Celular / Transplante de Fígado / Regeneração Hepática Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article