2. Academic Validation
  3. p38γ is essential for cell cycle progression and liver tumorigenesis

p38γ is essential for cell cycle progression and liver tumorigenesis

  • Nature. 2019 Apr;568(7753):557-560. doi: 10.1038/s41586-019-1112-8.
Antonia Tomás-Loba 1,  Elisa Manieri # 1 2,  Bárbara González-Terán # 1,  Alfonso Mora 1,  Luis Leiva-Vega 1,  Ayelén M Santamans 1,  Rafael Romero-Becerra 1,  Elena Rodríguez 1,  Aránzazu Pintor-Chocano 1,  Ferran Feixas 3,  Juan Antonio López 1,  Beatriz Caballero 1,  Marianna Trakala 4,  Óscar Blanco 5,  Jorge L Torres 5,  Lourdes Hernández-Cosido 5,  Valle Montalvo-Romeral 1,  Nuria Matesanz 1,  Marta Roche-Molina 1,  Juan Antonio Bernal 1,  Hannah Mischo 6,  Marta León 1,  Ainoa Caballero 1,  Diego Miranda-Saavedra 7 8,  Jesús Ruiz-Cabello 1 9 10 11 12,  Yulia A Nevzorova 13 12,  Francisco Javier Cubero 14 15,  Jerónimo Bravo 16,  Jesús Vázquez 1 17,  Marcos Malumbres 4,  Miguel Marcos 5,  Sílvia Osuna 3 18,  Guadalupe Sabio 19
Affiliations

Affiliations

  • 1 Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
  • 2 Centro Nacional de Biotecnología, CSIC, Madrid, Spain.
  • 3 Departament de Química and Institut de Química Computacional i Catàlisi, Universitat de Girona, Girona, Spain.
  • 4 Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
  • 5 University of Salamanca, University Hospital of Salamanca-IBSAL, Salamanca, Spain.
  • 6 Sir William Dunn School of Pathology, Oxford University, Oxford, UK.
  • 7 Centro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid, Madrid, Spain.
  • 8 University of Oxford Wolfson Building, Oxford, UK.
  • 9 CIC biomaGUNE, 2014, Donostia-San Sebastián, Spain.
  • 10 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
  • 11 Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
  • 12 Faculty of Biology, Complutense University, Madrid, Spain.
  • 13 University Hospital RWTH Aachen, Aachen, Germany.
  • 14 Complutense University School of Medicine, Madrid, Spain.
  • 15 12 de Octubre Health Research Institute (imas12), Madrid, Spain.
  • 16 Instituto de Biomedicina de Valencia, IBV-CSIC, Valencia, Spain.
  • 17 CIBER Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
  • 18 ICREA, Barcelona, Spain.
  • 19 Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. [email protected].
  • # Contributed equally.
PMID: 30971822 DOI: 10.1038/s41586-019-1112-8
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.

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