Suchergebnisse

The p38 MAPK pathway is well known for its role in transducing stress signals from the environment. Many key players and regulatory mechanisms of this signaling cascade have been described to some extent. Nevertheless, p38 participates in a broad range of cellular activities, for many of which detailed molecular pictures are still lacking. Originally described as a tumor-suppressor kinase for its inhibitory role in RAS-dependent transformation, p38 can also function as a tumor promoter, as demonstrated by extensive experimental data. This finding has prompted the development of specific inhibitors that have been used in clinical trials to treat several human malignancies, although without much success to date. However, elucidating critical aspects of p38 biology, such as isoform-specific functions or its apparent dual nature during tumorigenesis, might open up new possibilities for therapy with unexpected potential. In this review, we provide an extensive description of the main biological functions of p38 and focus on recent studies that have addressed its role in cancer. Furthermore, we provide an updated overview of therapeutic strategies targeting p38 in cancer and promising alternatives currently being explored. ; This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2017-85152-P and FEDER to E.d.N and PGC2018-094136-B-I00 and FEDER to F.P.], the AECC Foundation [PROYE18010POSA to F.P.) and the Catalan Government (2017 SGR 799 to E.d.N and F.P.). F.P. is a recipient of an ICREA Acadèmia award (Catalan Government). We gratefully acknowledge institutional funding from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) through the Centres of Excellence Severo Ochoa award, from the CERCA Programme of the Catalan Government, and from "Unidad de Excelencia María de Maeztu," funded by the AEI (CEX2018-000792-M).

Alternative splicing is a prevalent mechanism of gene regulation that is modulated in response to a wide range of extracellular stimuli. Stress-activated protein kinases (SAPKs) play a key role in controlling several steps of mRNA biogenesis. Here, we show that osmostress has an impact on the regulation of alternative splicing (AS), which is partly mediated through the action of p38 SAPK. Splicing network analysis revealed a functional connection between p38 and the spliceosome component SKIIP, whose depletion abolished a significant fraction of p38-mediated AS changes. Importantly, p38 interacted with and directly phosphorylated SKIIP, thereby altering its activity. SKIIP phosphorylation regulated AS of GADD45α, the upstream activator of the p38 pathway, uncovering a negative feedback loop involving AS regulation. Our data reveal mechanisms and targets of SAPK function in stress adaptation through the regulation of AS. ; This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2015-64437-P and FEDER, PGC2018-094136-B-I00 and FEDER, BFU2014-52125-REDT, and BFU2014-51672-REDC to F.P.; BFU2017-85152-P and FEDER to E.d.N.; BFU2014-005153 to J.V.), the Catalan Government (2017 SGR 799), the European Research Council (AdvG 670146 to J.V.), the Fundación Botín and the Banco Santander through its Santander Universities Global Division (to F.P. and J.V.), the Unidad de Excelencia Maria de Maeztu (MDM-2014-0370), and the Centre of Excellence Severo Ochoa. F.P. is a recipient of an ICREA Acadèmia (Generalitat de Catalunya).