JCAD deficiency delayed liver regenerative repair through the Hippo-YAP signalling pathway
© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Clinical and translational medicine - 14(2024), 3 vom: 20. März, Seite e1630 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Li [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.03.2024 Date Revised 17.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1002/ctm2.1630 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a JCAD deficiency delayed liver regenerative repair through the Hippo-YAP signalling pathway |
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| 500 | |a Date Revised 17.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Hippo–YAP signalling pathway | |
| 650 | 4 | |a JCAD | |
| 650 | 4 | |a WWC1 | |
| 650 | 4 | |a cell cycle phase visualisation | |
| 650 | 4 | |a liver regeneration | |
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| 650 | 7 | |a Protein Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Proteins |2 NLM | |
| 650 | 7 | |a WWC1 protein, human |2 NLM | |
| 650 | 7 | |a JCAD protein, mouse |2 NLM | |
| 650 | 7 | |a Cell Adhesion Molecules |2 NLM | |
| 700 | 1 | |a Yang, Yong-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhong, Zhenxing |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zhong-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yu-Li |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xiu-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Fa-Xing |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Jian |e verfasserin |4 aut | |
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