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p38γ is essential for cell cycle progression and liver tumorigenesis

2019; Nature Portfolio; Volume: 568; Issue: 7753 Linguagem: Inglês

10.1038/s41586-019-1112-8

1476-4687

Antonia Tomás‐Loba, Elisa Manieri, Bárbara González‐Terán, Alfonso Mora, Luis Leiva‐Vega, Ayelén M. Santamans, Rafael Romero-Becerra, Elena M. Rodríguez Rodríguez, Aránzazu Pintor‐Chocano, Ferran Feixas, Juan Antonio López, Beatriz Caballero, Marianna Trakala, Óscar Blanco, Jorge Torres, Lourdes Hernández‐Cosido, Valle Montalvo-Romeral, Nuria Matesanz, Marta Roche-Molina, Juan A. Bernal, Hannah E. Mischo, Marta León, Ainoa Caballero, Diego Miranda‐Saavedra, Jesús Ruíz‐Cabello, Yulia A. Nevzorova, Francisco Javier Cubero, Jerónimo Bravo, Jesús Vázquez, Marcos Malumbres, Miguel Marcos, Sílvia Osuna, Guadalupe Sabio,

Ubiquitin and proteasome pathways

The cell cycle is a tightly regulated process that is controlled by the conserved cyclin-dependent kinase (CDK)–cyclin protein complex1. 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. The stress-activated kinase p38γ has a role in regulating entry into the cell cycle; in the liver, it can induce cellular proliferation during regeneration and promote the development of hepatocellular carcinoma.