Role of stress-activated protein kinase p38MAPK in human diseases



Ana Cuenda

Group Leader


Asociated Scientist: Lourdes Planelles

Research summary

The aim of our group is both to discover how members of the p38MAPKfamily regulate cellular function in physiological conditions and in response to environmental stresses, infection and proinflammatory cytokines, and to understand how they become deregulated in several human disease situations such as oncogenic transformation and inflammation.




Alsina‐Beauchamp D, Escós A, Fajardo P, González‐Romero D, E Díaz‐Mora, Risco A, Martín‐Serrano MA, del Fresno C, Dominguez‐Andrés J, Aparicio N, Zur R, Shpiro N, Brown GD, Ardavín C, Netea MG, Alemany S, Sanz‐Ezquerro JJ, Cuenda A. Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity. EMBO Mol Med 2018; e8485; DOI 10.15252/emmm.201708485

Cuenda A, Sanz-Ezquerro JJ. p38γ and p38δ: From Spectators to Key Physiological Players. Trends Biochem Sci. 2017; 42(6):431-442

Dayalan Naidu S, Sutherland C, Zhang Y, Risco A, de la Vega L, Caunt CJ, Hastie CJ, Lamont DJ, Torrente L, Chowdhry S, Benjamin IJ, Keyse SM, Cuenda A, Dinkova-Kostova AT. Heat Shock Factor 1 Is a Substrate for p38 Mitogen-Activated Protein Kinases. Mol Cell Biol. 2016; 36(18):2403-17

Zur R, Garcia-Ibanez L, Nunez-Buiza A, Aparicio N, Liappas G, Escós A, Risco A, Page A, Saiz-Ladera C, Alsina-Beauchamp D, Montans J, Paramio JM, Cuenda A. Combined deletion of p38γ and p38δ reduces skin inflammation and protects from carcinogenesis. Oncotarget. 2015 May 30;6(15):12920-35

Criado G, Risco A, Alsina-Beauchamp D, Pérez-Lorenzo MJ, Escós A, Cuenda A. Alternative p38 mitogen-activated protein kinases are essential for collagen-induced arthritis. Arthritis Rheumatol 2014; 66:1208-1217


Figure 1Our group studies the physiological and pathological functions of the p38MAPK family of mitogen-activated protein kinases. Our research focuses on:

• the discovery of new substrates, interacting proteins and inhibitors for these kinases, as well as study of their physiological roles using mice transgenic for distinct p38 isoforms, and

• the study of p38MAPK as a link between chronic inflammation and cancer, and as mediators of chronic inflammatory diseases.

Inflammation stands at the centre of many pathological (cancer) and natural (tissue repair) processes. It is well known that, in the right place and at the right time, controls a healthy host response, but uncontrolled inflammation is pathological. The main goal of this proposal is to expand our knowledge of the molecular mechanisms involved in the inflammatory response in the settings of: 1) chronic inflammation leading to tumour development (as in colon cancer associated to colitis); 2) pathogen infection by Candida albicans and 3) normal inflammatory resolution occurring in tissue repair/regeneration.

We are currently undertaking further studies to investigate the role of p38γ and p38δ in those processes. Our studies utilize biochemical, cell biology as well as whole animal model approaches using the genetically modified mice we have generated. Additionally, we are investigating the mechanism of p38γ and p38δ activation by inflammation and by pathogen infection, and how p38γ and p38δ regulation of cytokine and chemokine production in innate immune cells regulates inflammatory responses.

In the collagen-induced arthritis (CIA) model of chronic inflammation, we showed that combined p38γ and p38δ deficiency markedly reduced arthritis severity and suppressed clinical disease, synovial inflammation and bone destruction compared with that in WT (wild-type) mice. Reduced disease severity in p38γ/δ-null mice was associated with lower cytokine production, T cell proliferation and anti-collagen antibody responses than in controls, indicating that p38γ and p38δ are crucial regulators of inflammatory joint destruction in CIA. We proposed p38γ and p38δ as potential therapeutic targets in complex diseases, such as rheumatoid arthritis, that involve innate and adaptive immune responses.

Chronic inflammation is a known risk factor for tumourigenesis. We analysed the role of p38γ and p38δ in colitis-associated colon cancer using the azoxymethane/dextran sodium sulphate colitis-associated colorectal cancer model. We found that p38γ/δ deficiency decreased tumour formation significantly, in parallel with decreased production of proinflammatory cytokines and chemokines. Analysis of leukocyte populations in p38γ/δ-null mouse colon showed less macrophage and neutrophil recruitment than in WT mice. WT chimeric mice with transplanted p38γ/δ-/- bone marrow (BM) had fewer tumours than WT mice transplanted with WT BM, whereas tumour number increased significantly in p38γ/δ-/- chimeric mice with WT BM compared to p38γ/δ-/- mice that received p38γ/δ-/- BM. Our results establish that p38γ and p38δ are central to colon inflammation-induced tumour formation by regulating hematopoietic cell response to injury, and validate p38γ and p38δ as potential targets for cancer therapy.


Figure 2


Ana Cuenda Principal investigator
Ana Risco Postdoctoral scientist
Alejandra Escós Predoctoral scientist
Miguel Angel Martín Predoctoral scientist
David Monedero Predoctoral scientist
Ruth Gómez-Caro Technician
Jose Maria Ballestero Technician

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