p38γ is essential for cell cycle progression and liver tumorigenesis

Antonia Tomás-Loba, Elisa Manieri, Bárbara González-Terán, Alfonso Mora, Luis Leiva-Vega, Ayelén M. Santamans, Rafael Romero-Becerra, Elena Rodríguez, Aránzazu Pintor-Chocano, Ferran Feixas, Juan Antonio López, Beatriz Caballero, Marianna Trakala, Óscar Blanco, Jorge L. Torres, Lourdes Hernández-Cosido, Valle Montalvo-Romeral, Nuria Matesanz, Marta Roche-Molina, Juan Antonio Bernal, Hannah Mischo, Marta León, Ainoa Caballero, Diego Miranda-Saavedra, Jesús Ruiz-Cabello, Yulia A. Nevzorova, Francisco Javier Cubero, Jerónimo Bravo, Jesús Vázquez, Marcos Malumbres, Miguel Marcos, Sílvia Osuna and Guadalupe Sabio ()
Additional contact information
Antonia Tomás-Loba: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Elisa Manieri: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Bárbara González-Terán: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Alfonso Mora: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Luis Leiva-Vega: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Ayelén M. Santamans: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Rafael Romero-Becerra: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Elena Rodríguez: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Aránzazu Pintor-Chocano: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Ferran Feixas: Universitat de Girona
Juan Antonio López: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Beatriz Caballero: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Marianna Trakala: Centro Nacional de Investigaciones Oncológicas (CNIO)
Óscar Blanco: University of Salamanca, University Hospital of Salamanca-IBSAL
Jorge L. Torres: University of Salamanca, University Hospital of Salamanca-IBSAL
Lourdes Hernández-Cosido: University of Salamanca, University Hospital of Salamanca-IBSAL
Valle Montalvo-Romeral: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Nuria Matesanz: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Marta Roche-Molina: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Juan Antonio Bernal: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Hannah Mischo: Oxford University
Marta León: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Ainoa Caballero: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Diego Miranda-Saavedra: CSIC/Universidad Autónoma de Madrid
Jesús Ruiz-Cabello: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Yulia A. Nevzorova: University Hospital RWTH Aachen
Francisco Javier Cubero: Complutense University School of Medicine
Jerónimo Bravo: Instituto de Biomedicina de Valencia, IBV-CSIC
Jesús Vázquez: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Marcos Malumbres: Centro Nacional de Investigaciones Oncológicas (CNIO)
Miguel Marcos: University of Salamanca, University Hospital of Salamanca-IBSAL
Sílvia Osuna: Universitat de Girona
Guadalupe Sabio: Centro Nacional de Investigaciones Cardiovasculares (CNIC)

Nature, 2019, vol. 568, issue 7753, 557-560

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1112-8

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