p38γ is essential for cell cycle progression and liver tumorigenesis.

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.G.S. (RYC-2009-04972), F.J.C. (RYC-2014-15242), and Y.A.N. (RYC-2015-17438) are investigators of the Ramón y Cajal Program. E.M. and M.T. were awarded La Caixa fellowships and R.R.-B. was a fellow of the Fundación Ramón Areces-UAM and FPU. B.G.-T. is a fellow of the FPI Severo Ochoa CNIC program (SVP-2013-067639). F.J.C. is a Gilead Liver Research Scholar. This work was funded by grants supported in part by funds from the European Regional Development Fund: the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC 260464, EFSD/Lilly European Diabetes Research Programme Dr Sabio, 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (InvestigadoresBBVA-2017) IN[17]_BBM_BAS_0066, MINECO-FEDER SAF2016-79126-R, and Comunidad de Madrid IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/ BMD-3733 to G.S.; Juan de la Cierva and MINECO SAF2014-61233-JIN to A.T.-L.; the European Community for MSCA-IF-2014-EF-661160-MetAccembly grant to F.F.; Spanish MINECO CTQ2014-59212-P, European Community for CIG project (PCIG14-GA-2013-630978), and European Research Council (ERC) under the European Union’s Horizon 2020 (ERC-2015-StG-679001- NetMoDEzyme) to S.O.; the German Research Foundation (SFB/TRR57/P04 and DFG NE 2128/2-1) and MINECO SAF2017-87919R to Y.A.N.; EXOHEP-CM S2017/BMD-3727 and the COST Action CA17112, MINECO SAF2016-78711, and the AMMF Cholangiocarcinoma Charity 2018/117 to F.J.C.; MINECO (SAF2015-69920-R co-funded by ERDF-EU), the Consolider-Ingenio 2010 Programme (SAF2014-57791-REDC), Excellence Network CellSYS (BFU2014- 52125-REDT), and the iLUNG Programme (B2017/BMD-3884) from the Comunidad de Madrid to M. Malumbres; MINECO SAF2015-67077-R and SAF2017-89901-R to J.B.; MINECO (BIO2015-67580-P), Carlos III Institute of Health-Fondo de Investigación Sanitaria (ProteoRed PRB3, IPT17/0019 - ISCIII-SGEFI/ERDF), Fundación La Marató and ‘La Caixa’ Banking Foundation (HR17-00247) to J.V.; ISCIII and FEDER PI16/01548 and Junta de Castilla y León GRS 1362/A/16 and INT/M/17/17 to M. Marcos; Junta de Castilla y León GRS 1356/A/16 and GRS 1587/A/17 to J.L.-T.; and MCNU (SAF2017- 84494-C2-1-R) to J.R.-C. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S