Article

P38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta

MRC Protein Phosphorylation Unit, College of life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 09/2007; 1773(8):1358-75. DOI: 10.1016/j.bbamcr.2007.03.010
Source: PubMed

ABSTRACT Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by a wide range of cellular stresses as well as in response to inflammatory cytokines. There are four members of the p38MAPK family (p38alpha, p38beta, p38gamma and p38delta) which are about 60% identical in their amino acid sequence but differ in their expression patterns, substrate specificities and sensitivities to chemical inhibitors such as SB203580. A large body of evidences indicates that p38MAPK activity is critical for normal immune and inflammatory response. The p38MAPK pathway is a key regulator of pro-inflammatory cytokines biosynthesis at the transcriptional and translational levels, which makes different components of this pathway potential targets for the treatment of autoimmune and inflammatory diseases. However, recent studies have shed light on the broad effect of p38MAPK activation in the control of many other aspects of the physiology of the cell, such as control of cell cycle or cytoskeleton remodelling. Here we focus on these emergent roles of p38MAPKs and their implication in different pathologies.

Download full-text

Full-text

Available from: Ana Cuenda, Aug 19, 2015
3 Followers
 · 
168 Views
  • Source
    • "MAPKs are a superfamily of proline-directed serine/threonine protein kinases [42], which include extracellular signal regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38. The MAPK pathways transduce a large variety of external signals, leading to a wide range of cellular responses , including growth, differentiation, inflammation, and apoptosis [43]. The results in the present study showed that EGCGtreated SAS cells significantly induced the p38 phosphorylation in a dose-dependent manner and activated JNK and ERK at doses of 12.5 μM and 25 μM EGCG treatments. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oral squamous cell carcinoma (OSCC) is a well-known malignancy that accounts for the majority of oral cancers. B-cell translocation gene 2 (BTG2) is an important regulator of cell cycle dynamics in cancer cells. However, the role of BTG2 in OSCC cells and the influences of epigallocatechin-3-gallate (EGCG) on BTG2 gene expressions have not been well evaluated. The objectives of this study were to examine the effect of EGCG-induced BTG2 expression and the potential signal pathways involved. The (3)H-thymidine incorporation and Western-blot assays revealed cell proliferation was attenuated by EGCG via upregulation of BTG2 expression causing cell cycle G1 phase arrest in OSCC cells. BTG2 overexpression decreased tumor cell growth, while BTG2 knockdown illuminated the opposite effect in xenograft animal studies. Overexpressed BTG2 arrested the cell cycle at the G1 phase and downregulated protein expressions of cyclin A, cyclin D, and cyclin E. Western-blot assays indicated that EGCG induced phosphorylation of p38, JNK, and ERK. However, pretreatments with selective mitogen-activated protein kinases (MAPKs) inhibitors, SB203580 (p38 inhibitor) and PD0325901 (ERK1/2 inhibitor), significantly suppressed the activation of EGCG on BTG2 expression. Our results indicate that EGCG attenuates cell proliferation of OSCC cells by upregulating BTG2 expression via p38 and ERK pathways. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer Letters 02/2015; 360(2). DOI:10.1016/j.canlet.2015.02.034 · 5.62 Impact Factor
  • Source
    • "Hypomethylated DMRs also mapped to a strikingly high number of genes encoding enzymes of the mitogen-activated protein kinase (MAPK) family. In particular, we identified members of the p38 MAPK pathway, a signaling cascade involved in many autoimmune diseases (Cuenda and Rousseau, 2007). Also, this pathway is implicated in many processes in CD4+ T cells (Dodeller et al., 2005), including integration of extracellular signals, T cell activation and differentiation and production of proinflammatory cytokines (Mavropoulos et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autoimmune Addison's Disease (AAD) is an endocrine and immunological disease of uncertain pathogenesis resulting from the immune system's destruction of the hormone producing cells of the adrenal cortex. The underlying molecular mechanisms are largely unknown, but it is commonly accepted that a combination of genetic susceptibility and environmental impact is critical. In the present study, we identified multiple hypomethylated gene promoter regions in patients with isolated AAD using DNA isolated from CD4+ T cells. The identified differentially methylated regions were distributed evenly across the 10.5-kb-promoter regions covered by the array, and a substantial number localized to promoters of genes involved in immune regulation and autoimmunity. This study reveals a hypomethylated status in CD4+ T cells from AAD patients and indicates differential methylation of promoters of key genes involved in immune responses.
    Molecular Immunology 06/2014; 59(2):208–216. DOI:10.1016/j.molimm.2014.02.018 · 3.00 Impact Factor
  • Source
    • "The present results indicate that a sudden temperature increase multiplied the expressions of proinflammatory cytokines in GBS-infected fish. Exposure to rapid temperature change can stimulate the expression of proinflammatory cytokines via the stress-dependent p38-MAPKs partway (Cuenda and Rousseau, 2007). However, in this study, the up-regulation decreased after 24 hpi in the challenged 35 8C group, which suggests that the fish had acclimated to the warmer temperature. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Temperature strongly affects the health of aquatic poikilotherms. In Nile tilapia (Oreochromis niloticus), elevated water temperatures increase the severity of streptococcosis. Here we investigated the effects of temperature on the vulnerability and inflammatory response of Nile tilapia to Streptococcus agalactiae (Group B streptococci; GBS). At 35 and 28°C, GBS took 4 and 7h, respectively to reach the log-phase and, when incubated with tilapia whole blood, experienced survival rates of 97% and 2%, respectively. The hemolysis activity of GBS grown at 35°C was five times higher than that of GBS grown at 28°C. GBS expressed cylE (β-hemolysin/cytolysin), cfb (CAMP factor) and PI-2b (pili-backbone) much more strongly at 35°C than at 28°C. Challenging Nile tilapia reared at 35 and 28°C with GBS resulted in accumulated mortalities of about 85% and 45%, respectively. At 35°C, infected tilapia exhibited tremendous inflammatory responses due to a dramatic up-regulation (30-40-fold) of inflammatory-related genes (cyclooxygenase-2, IL-1β and TNF-α) between 6 and 96h-post infection. These results suggest that the increase of GBS pathogenicity to Nile tilapia induced by elevated temperature is associated with massive inflammatory responses, which may lead to acute mortality.
    Veterinary Microbiology 04/2014; 172(1-2). DOI:10.1016/j.vetmic.2014.04.013 · 2.73 Impact Factor
Show more