Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Centro Nacional de Biotecnología, CSIC, Madrid, Spain.
Nature. 2019 Apr;568(7753):557-560. doi: 10.1038/s41586-019-1112-8. Epub 2019 Apr 10.
The cell cycle is a tightly regulated process that is controlled by the conserved cyclin-dependent kinase (CDK)-cyclin protein complex. However, control of the G0-to-G1 transition is not completely understood. Here we demonstrate that p38 MAPK gamma (p38γ) acts as a CDK-like kinase and thus cooperates with CDKs, regulating entry into the cell cycle. p38γ shares high sequence homology, inhibition sensitivity and substrate specificity with CDK family members. In mouse hepatocytes, p38γ induces proliferation after partial hepatectomy by promoting the phosphorylation of retinoblastoma tumour suppressor protein at known CDK target residues. Lack of p38γ or treatment with the p38γ inhibitor pirfenidone protects against the chemically induced formation of liver tumours. Furthermore, biopsies of human hepatocellular carcinoma show high expression of p38γ, suggesting that p38γ could be a therapeutic target in the treatment of this disease.
细胞周期是一个受到严格调控的过程，由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。然而，G0 到 G1 期转变的控制机制还不完全清楚。在这里，我们证明 p38 MAPK gamma (p38γ) 作为一种 CDK 样激酶发挥作用，因此与 CDKs 合作，调节细胞周期的进入。p38γ 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，p38γ 通过促进视网膜母细胞瘤肿瘤抑制蛋白在已知 CDK 靶位残基上的磷酸化，在部分肝切除后诱导增殖。缺乏 p38γ 或用 p38γ 抑制剂 pirfenidone 处理可防止化学诱导的肝肿瘤形成。此外，人类肝癌活检显示 p38γ 高表达，表明 p38γ 可能是治疗这种疾病的一个治疗靶点。
