Post-transcriptional gene regulation by MAP kinases via AU-rich elements.
ABSTRACT Eukaryotic cells must continuously sense their environments, for example their attachment to extracellular matrix and proximity to other cells, differences in temperature or redox conditions, the presence of nutrients, growth factors, hormones, cytokines or pathogens. The information must then be integrated and an appropriate response initiated by modulating the cellular programme of gene expression. The mitogen-activated protein kinase (MAPK) signaling pathways play a critical role in this process. Decades of research have illuminated the many ways in which MAPKs regulate the synthesis of mRNA (transcription) via phosphorylation of transcription factors, cofactors, and other proteins. In recent years it has become increasingly clear that the control of mRNA destruction is equally important for cellular responses to extracellular cues, and is equally subject to regulation by MAPKs. This review will summarize our current understanding of post-transcriptional regulation of gene expression by the MAPKs and the proteins that are involved in this process.
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ABSTRACT: Objective: Discuss recent cytokine findings in myofascial trigger points (MTrPs) in the context of known kinase cascades and other transduction pathways to determine what pharmacological and/or other manual therapy strategies might be useful to treat myofascial pain, and identify key biochemical entities to target future research. Methods: Search of the PubMed, Scopus, and Google databases for relevant key studies published since 1980 in English and German languages. Results: One hundred and thirteen articles were identified for inclusion into this narrative review. Discussion: Recent biochemical findings indicate a significant decrease in pH in active MTrPs compared to latent MTrPs or normal muscle, and large significant increases in cytokines, catecholamines, and neurotransmitters. The findings support Simons’ hypothesis, and it is possible that changes in bradykinin levels might in part be responsible for the pain experienced by patients with active MTrPs. There is also sufficient evidence to suggest that mitogen-activated protein kinases (MAPK) pathways might be involved with regard to myofascial pain and the development of MTrPs. MK2, a kinase downstream in p38 pathway has also been shown to be a point of convergence for multiple signaling processes activated during inflammation and has so far been targeted for various chronic inflammatory diseases. The potential efficiency of MK2 inhibitors is high because they may not only inhibit the production of inflammatory cytokines but also their actions. Finally, and most importantly, we still do not yet understand how latent MTrPs develop from normal muscle tissue and how latent MTrPs become active MTrPs. This must be an additional area of active research.International Musculoskeletal Medicine 01/2011; 33(2):64-74.
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ABSTRACT: p38 mitogen activated protein kinase (p38 MAPK) signaling plays a major role in the modulation of immune-mediated inflammatory responses and therefore has been linked with several autoimmune diseases. The extent of the involvement of p38 MAPK in the pathogenesis of autoimmune blistering diseases has started to emerge, but whether it pays a critical role is a matter of debate. The activity of p38 MAPK has been studied in great detail during the loss of keratinocyte cell-cell adhesions and the development of pemphigus vulgaris (PV) and pemphigus foliaceus (PF). These diseases are characterised by autoantibodies targeting desmogleins (Dsg). Whether autoantibody-antigen interactions can trigger signaling pathways (such as p38 MAPK) that are tightly linked to the secretion of inflammatory mediators which may perpetuate inflammation and tissue damage in pemphigus remains unclear. Yet, the ability of p38 MAPK inhibitors to block activation of the proapoptotic proteinase caspase-3 suggests that the induction of apoptosis may be a consequence of p38 MAPK activation during acantholysis in PV. This review discusses the current evidence for the role of p38 MAPK in the pathogenesis of pemphigus. We will also present data relating to the targeting of these cascades as a means of therapeutic intervention.Autoimmune diseases. 01/2013; 2013:728529.
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ABSTRACT: Human cytolytic T lymphocytes and natural killer cells can limit tumor growth and are being increasingly harnessed for tumor immunotherapy. One way cytolytic lymphocytes recognize tumor cells is by engagement of their activating receptor, NKG2D, by stress antigens of the MICA/B and ULBP families. This study shows that surface up-regulation of NKG2D ligands by human epithelial cells in response to ultraviolet irradiation, osmotic shock, oxidative stress, and growth factor provision is attributable to activation of the epidermal growth factor receptor (EGFR). EGFR activation causes intracellular relocalization of AUF1 proteins that ordinarily destabilize NKG2D ligand mRNAs by targeting an AU-rich element conserved within the 3' ends of most human, but not murine, NKG2D ligand genes. Consistent with these findings, NKG2D ligand expression by primary human carcinomas positively correlated with EGFR expression, which is commonly hyperactivated in such tumors, and was reduced by clinical EGFR inhibitors. Therefore, stress-induced activation of EGFR not only regulates cell growth but also concomitantly regulates the cells' immunological visibility. Thus, therapeutics designed to limit cancer cell growth should also be considered in terms of their impact on immunosurveillance.Science translational medicine 04/2014; 6(231):231ra49. · 10.76 Impact Factor