Capn3 depletion causes Chk1 and Wee1 accumulation and disrupts synchronization of cell cycle reentry during liver regeneration after partial hepatectomy  

作　　者：Feng Chen Delai Huang Hui Shi Ce Gao Yingchun Wang Jinrong Peng 

机构地区：[1]MOE Key Laboratory for Molecular Animal Nutrition,College of Animal Sciences,Zhejiang University,Hangzhou 310058,China [2]Present address:Department of Biology,University of Virginia,Charlottesville,VA,USA [3]Present address:Department of Pediatric Oncology,Dana-Farber Cancer Institute,Harvard Medical School,Boston,MA,USA [4]State Key Laboratory of Molecular Developmental Biology,Institute of Genetics and Developmental Biology,Chinese Academy of Sciences,Beijing 100101,China

出　　处：《Cell Regeneration》2020年第1期74-91,共18页细胞再生（英文）

基　　金：This study was supported by the National Key R&D Program of China and the Natural Science Foundation of China in the order of 2018YFA0800502,31830113 and 2017YFA0504501.

摘　　要：Recovery of liver mass to a healthy liver donor by compensatory regeneration after partial hepatectomy(PH)is a prerequisite for liver transplantation.Synchronized cell cycle reentry of the existing hepatocytes after PH is seemingly a hallmark of liver compensatory regeneration.Although the molecular control of the PH-triggered cell cycle reentry has been extensively studied,little is known about how the synchronization is achieved after PH.The nucleolus-localized protein cleavage complex formed by the nucleolar protein Digestive-organ expansion factor(Def)and cysteine proteinase Calpain 3(Capn3)has been implicated to control wounding healing during liver regeneration through selectively cleaving the tumor suppressor p53 in the nucleolus.However,whether the Def-Capn3 complex participates in regulating the synchronization of cell cycle reentry after PH is unknown.In this report,we generated a zebrafish capn3b null mutant(capn3b^(Δ19Δ14)).The homozygous mutant was viable and fertile,but suffered from a delayed liver regeneration after PH.Delayed liver regeneration in capn3b^(Δ19Δ14)was due to disruption of synchronized cell proliferation after PH.Mass spectrometry(MS)analysis of nuclear proteins revealed that a number of negative regulators of cell cycle are accumulated in the capn3b^(Δ19Δ14)liver after PH.Moreover,we demonstrated that Check-point kinase 1(Chk1)and Wee1,two key negative regulators of G2 to M transition,are substrates of Capn3.We also demonstrated that Chk1 and Wee1 were abnormally accumulated in the nucleoli of amputated capn3bΔ19Δ14 liver.In conclusion,our findings suggest that the nucleolar-localized Def-Capn3 complex acts as a novel regulatory pathway for the synchronization of cell cycle reentry,at least partially,through inactivating Chk1 and Wee1 during liver regeneration after PH.

关 键 词：Def Capn3 CHK1 Wee1 NUCLEOLUS Cell cycle Liver regeneration Partial hepatectomy ZEBRAFISH 

分 类 号：R73[医药卫生—肿瘤]