信号转导衔接蛋白
调节器
GRB2型
癌症研究
生物
细胞生物学
计算生物学
信号转导
遗传学
基因
作者
Xiaoyan Wu,Yuwen Zhu,Yan Guo,Zhigang Zhao,Zheng Li
出处
期刊:Life Sciences
[Elsevier]
日期:2023-08-01
卷期号:327: 121861-121861
被引量:2
标识
DOI:10.1016/j.lfs.2023.121861
摘要
Excessive liver fibrosis is frequently observed in chronic liver diseases and associated with decline of liver functions. Hepatic stellate cells (HSCs) are considered the principal mediator of liver fibrosis by trans-differentiating into myofibroblasts. In the present study we investigated the role of Grb2-related adaptor protein (GRAP) in HSC activation and liver fibrosis. Liver fibrosis was induced by carbon tetrachloride (CCl4) injection. Gene expression was examined by quantitative PCR. Cell proliferation was evaluated by EdU incorporation. DNA-protein interaction was examined by chromatin immunoprecipitation (ChIP). GRAP expression was up-regulated during HSC-myofibroblast transition both in vivo and in vitro. Mechanistically, serum response factor (SRF) and myocardin-related transcription factor A (MRTF-A) formed a complex to bind to the GRAP promoter and activate GRAP transcription. Small interfering RNA (siRNA) mediated GRAP silencing blocked HSC-myofibroblast transition in vitro. Importantly, adeno-associated virus 6 (AAV6) mediated GRAP knockdown in myofibroblasts attenuated liver fibrosis in mice. Of note, inhibition of ERK signaling abrogated enhancement of HSC-myofibroblast transition by GRAP over-expression. Our data suggest that GRAP, possibly via ERK activation, regulates HSC-myofibroblast transition and contributes to liver fibrosis. Screening for small-molecule GRAP inhibitors may yield novel therapeutic solutions against liver fibrosis.
科研通智能强力驱动
Strongly Powered by AbleSci AI