Cuenda, A. & Rousseau, S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim. Biophys. Acta 1773, 1358-1375

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


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.

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    • "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. "
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    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
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    • "Deletion of p38α during embryogenesis affected intramembranous calvarial bone development as early as on postnatal day 7. Similarly long bones arising from endochondral ossification also showed an important reduction in both trabecular and cortical bone at very early developmental stages. So far no major differences in substrates and transcriptional targets activated by p38α or p38β have been shown, suggesting their functional redundancy [49]. It could thus be hypothesized that the relative role of these two subunits would largely depend on their differential tissue expression and/or activity in osteoblast cells. "
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    ABSTRACT: Background p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified. Methodology/Principal Findings We evaluated osteoblast-specific deletion of p38α to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38α deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38α did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38α disruption after birth by removal of doxycycline. Deletion of p38α at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months. Conclusions Our data demonstrates that, in addition to early skeletogenesis, p38α is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects.
    PLoS ONE 07/2014; 9(7):e102032. DOI:10.1371/journal.pone.0102032 · 3.23 Impact Factor
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    • "The p38 mitogen-activated protein kinases are also activated by different cellular stresses, bacterial lipopolysaccharide (LPS) and inflammatory cytokines, including IL-1β [81]. These kinases are also involved in the regulation of pro-inflammatory cytokine expression [82]. There are four p38 MAPKs identified so far: MAPK14/p38-α/SAPK2A, MAPK11/p38-β/SAPK2B, MAPK12/p38-γ/SAPK3 and MAPK13/p38-δ/SAPK4. "
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    ABSTRACT: Patients with cystic fibrosis (CF) have elevated concentration of cytokines in sputum and a general inflammatory condition. In addition, CF cells in culture produce diverse cytokines in excess, including IL-1β. We have previously shown that IL-1β, at low doses (∼30 pM), can stimulate the expression of CFTR in T84 colon carcinoma cells, through NF-κB signaling. However, at higher doses (>2.5 ng/ml, ∼150 pM), IL-1β inhibit CFTR mRNA expression. On the other hand, by using differential display, we found two genes with reduced expression in CF cells, corresponding to the mitochondrial proteins CISD1 and MTND4. The last is a key subunit for the activity of mitochondrial Complex I (mCx-I); accordingly, we later found a reduced mCx-I activity in CF cells. Here we found that IB3-1 cells (CF cells), cultured in serum-free media, secrete 323±5 pg/ml of IL-1β in 24 h vs 127±3 pg/ml for S9 cells (CFTR-corrected IB3-1 cells). Externally added IL-1β (5 ng/ml) reduces the mCx-I activity and increases the mitochondrial (MitoSOX probe) and cellular (DCFH-DA probe) ROS levels of S9 (CFTR-corrected IB3-1 CF cells) or Caco-2/pRSctrl cells (shRNA control cells) to values comparable to those of IB3-1 or Caco-2/pRS26 cells (shRNA specific for CFTR). Treatments of IB3-1 or Caco-2/pRS26 cells with either IL-1β blocking antibody, IL-1 receptor antagonist, IKK inhibitor III (NF-κB pathway) or SB203580 (p38 MAPK pathway), restored the mCx-I activity. In addition, in IB3-1 or Caco-2/pRS26 cells, IL-1β blocking antibody, IKK inhibitor III or SB203580 reduced the mitochondrial ROS levels by ∼50% and the cellular ROS levels near to basal values. The AP-1 inhibitors U0126 (MEK1/2) or SP600125 (JNK1/2/3 inhibitor) had no effects. The results suggest that in these cells IL-1β, through an autocrine effect, acts as a bridge connecting the CFTR with the mCx-I activity and the ROS levels.
    PLoS ONE 06/2014; 9(6):e99257. DOI:10.1371/journal.pone.0099257 · 3.23 Impact Factor
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