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; Guadalupe Sabio

doi:10.1038/s41586-019-1112-8

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 BernalHannah 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, Guadalupe Sabio

Infectious Diseases

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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.

Original language	English
Pages (from-to)	557-560
Journal	Nature
Volume	568
Issue number	7753
Early online date	10 Apr 2019
DOIs	https://doi.org/10.1038/s41586-019-1112-8
Publication status	Published - 25 Apr 2019

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p38γ is essential for_TOMAS-LOBA_Acc7Mar2019Epub10Apr2019_GREEN AAMAccepted author manuscript, 5.58 MB

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Tomás-loba, A., Manieri, E., González-terán, B., Mora, A., Leiva-vega, L., Santamans, A. M., Romero-becerra, R., Rodríguez, E., Pintor-chocano, A., Feixas, F., López, J. A., Caballero, B., Trakala, M., Blanco, Ó., Torres, J. L., Hernández-cosido, L., Montalvo-romeral, V., Matesanz, N., Roche-molina, M., ... Sabio, G. (2019). p38γ is essential for cell cycle progression and liver tumorigenesis. Nature, 568(7753), 557-560. https://doi.org/10.1038/s41586-019-1112-8

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title = "p38γ is essential for cell cycle progression and liver tumorigenesis",

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.",

author = "Antonia Tom{\'a}s-loba and Elisa Manieri and B{\'a}rbara Gonz{\'a}lez-ter{\'a}n and Alfonso Mora and Luis Leiva-vega and Santamans, {Ayel{\'e}n M.} and Rafael Romero-becerra and Elena Rodr{\'i}guez and Ar{\'a}nzazu Pintor-chocano and Ferran Feixas and L{\'o}pez, {Juan Antonio} and Beatriz Caballero and Marianna Trakala and {\'O}scar Blanco and Torres, {Jorge L.} and Lourdes Hern{\'a}ndez-cosido and Valle Montalvo-romeral and Nuria Matesanz and Marta Roche-molina and Bernal, {Juan Antonio} and Hannah Mischo and Marta Le{\'o}n and Ainoa Caballero and Diego Miranda-saavedra and Jes{\'u}s Ruiz-cabello and Nevzorova, {Yulia A.} and Cubero, {Francisco Javier} and Jer{\'o}nimo Bravo and Jes{\'u}s V{\'a}zquez and Marcos Malumbres and Miguel Marcos and S{\'i}lvia Osuna and Guadalupe Sabio",

year = "2019",

month = apr,

day = "25",

doi = "10.1038/s41586-019-1112-8",

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Tomás-loba, A, Manieri, E, González-terán, B, Mora, A, Leiva-vega, L, Santamans, AM, Romero-becerra, R, Rodríguez, E, Pintor-chocano, A, Feixas, F, López, JA, Caballero, B, Trakala, M, Blanco, Ó, Torres, JL, Hernández-cosido, L, Montalvo-romeral, V, Matesanz, N, Roche-molina, M, Bernal, JA, Mischo, H, León, M, Caballero, A, Miranda-saavedra, D, Ruiz-cabello, J, Nevzorova, YA, Cubero, FJ, Bravo, J, Vázquez, J, Malumbres, M, Marcos, M, Osuna, S & Sabio, G 2019, 'p38γ is essential for cell cycle progression and liver tumorigenesis', Nature, vol. 568, no. 7753, pp. 557-560. https://doi.org/10.1038/s41586-019-1112-8

TY - JOUR

T1 - p38γ is essential for cell cycle progression and liver tumorigenesis

AU - Tomás-loba, Antonia

AU - Manieri, Elisa

AU - González-terán, Bárbara

AU - Mora, Alfonso

AU - Leiva-vega, Luis

AU - Santamans, Ayelén M.

AU - Romero-becerra, Rafael

AU - Rodríguez, Elena

AU - Pintor-chocano, Aránzazu

AU - Feixas, Ferran

AU - López, Juan Antonio

AU - Caballero, Beatriz

AU - Trakala, Marianna

AU - Blanco, Óscar

AU - Torres, Jorge L.

AU - Hernández-cosido, Lourdes

AU - Montalvo-romeral, Valle

AU - Matesanz, Nuria

AU - Roche-molina, Marta

AU - Bernal, Juan Antonio

AU - Mischo, Hannah

AU - León, Marta

AU - Caballero, Ainoa

AU - Miranda-saavedra, Diego

AU - Ruiz-cabello, Jesús

AU - Nevzorova, Yulia A.

AU - Cubero, Francisco Javier

AU - Bravo, Jerónimo

AU - Vázquez, Jesús

AU - Malumbres, Marcos

AU - Marcos, Miguel

AU - Osuna, Sílvia

AU - Sabio, Guadalupe

PY - 2019/4/25

Y1 - 2019/4/25

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-019-1112-8

DO - 10.1038/s41586-019-1112-8

M3 - Article

SN - 0028-0836

VL - 568

SP - 557

EP - 560

JO - Nature

JF - Nature

IS - 7753

ER -

p38γ is essential for cell cycle progression and liver tumorigenesis

Abstract

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