p38γ is essential for cell cycle progression and liver tumorigenesis
p38γ is essential for cell cycle progression and liver tumorigenesis
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DOI：
10.1038/s41586-019-1112-8
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发表时间：
2019-04-25
期刊：
影响因子：
64.8
通讯作者：
Sabio, Guadalupe
中科院分区：
文献类型：
--
作者：
Tomas-Loba, Antonia;Manieri, Elisa;Sabio, Guadalupe
细胞周期是一个受保守的细胞周期蛋白依赖性激酶（CDK）-细胞周期蛋白复合物控制的严格调控过程（1）。然而，对G 0到G1转变的控制还没有完全理解。在这里，我们证明，p38 MAPK γ（p38 γ）作为一个CDK样激酶，从而与CDK合作，调节进入细胞周期。p38 γ与CDK家族成员具有高度的序列同源性、抑制敏感性和底物特异性。在小鼠肝细胞中，p38 γ通过促进视网膜母细胞瘤肿瘤抑制蛋白在已知CDK靶残基处的磷酸化来诱导部分肝切除术后的增殖。缺乏p38 γ或用p38 γ抑制剂吡非尼酮治疗可防止化学诱导的肝肿瘤形成。此外，人肝细胞癌的活检显示p38 γ的高表达，表明p38 γ可能是治疗这种疾病的治疗靶点。
The cell cycle is a tightly regulated process that is controlled by the conserved cyclin-dependent kinase (CDK)-cyclin protein complex(1). However, control of the G0-to-G1 transition is not completely understood. Here we demonstrate that p38 MAPK gamma (p38 gamma) acts as a CDK-like kinase and thus cooperates with CDKs, regulating entry into the cell cycle. p38 gamma shares high sequence homology, inhibition sensitivity and substrate specificity with CDK family members. In mouse hepatocytes, p38 gamma induces proliferation after partial hepatectomy by promoting the phosphorylation of retinoblastoma tumour suppressor protein at known CDK target residues. Lack of p38 gamma or treatment with the p38 gamma inhibitor pirfenidone protects against the chemically induced formation of liver tumours. Furthermore, biopsies of human hepatocellular carcinoma show high expression of p38 gamma, suggesting that p38 gamma could be a therapeutic target in the treatment of this disease.