Post-transcriptional gene regulation by MAP kinases via AU-rich elements

Kennedy Institute of Rheumatology Division, Imperial College London, 1 Aspenlea Road, Hammersmith, London W6 8LH, UK.
Frontiers in Bioscience (Impact Factor: 4.25). 02/2009; 14:847-71.
Source: PubMed

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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    • "Transcription is further regulated by the binding of sequence-specific repressor and activator proteins (transcription factors) to DNA elements and/or to the transcription machinery at promoters. The quantitative importance of posttranscriptional mechanisms in the regulation of protein concentrations and activities is becoming increasingly clear (Clark et al., 2009; Daran-Lapujade et al., 2004; Day and Tuite, 1998; Haanstra et al., 2008; Kolkman et al., 2006). In many eukaryotes, the first events after transcription are mRNA splicing and the transport of mRNA molecules from the nucleus to the cytosol, both of which can be regulated (Licatalosi and Darnell, 2010). "
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    ABSTRACT: Regulation analysis is a methodology that quantifies to what extent a change in the flux through a metabolic pathway is regulated by either gene expression or metabolism. Two extensions to regulation analysis were developed over the past years: (i) the regulation of V(max) can be dissected into the various levels of the gene-expression cascade, such as transcription, translation, protein degradation, etc. and (ii) a time-dependent version allows following flux regulation when cells adapt to changes in their environment. The methodology of the original form of regulation analysis as well as of the two extensions will be described in detail. In addition, we will show what is needed to apply regulation analysis in practice. Studies in which the different versions of regulation analysis were applied revealed that flux regulation was distributed over various processes and depended on time, enzyme, and condition of interest. In the case of the regulation of glycolysis in baker's yeast, it appeared, however, that cells that remain under respirofermentative conditions during a physiological challenge tend to invoke more gene-expression regulation, while a shift between respirofermentative and respiratory conditions invokes an important contribution of metabolic regulation. The complexity of the regulation observed in these studies raises the question what is the advantage of this highly distributed and condition-dependent flux regulation.
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    • "The transmission of signals to the latter compartment is important for the common role of the cascade, namely the induction and regulation of de-novo gene expression [8]. For this purpose, the signals transmitted via the different cascades need to be transported across the nuclear envelope and modulate the activity of a large number of transcription factors, transcription suppressors, and chromatin remodeling proteins, to secure the proper cellular responses [9] [10]. The transmission of signals to the nucleus is mediated mostly by a stimulated physical translocation of components of the MAPK cascade into the nucleus. "
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    ABSTRACT: The MAPK cascades are central signaling pathways that regulate a wide variety of stimulated cellular processes, including proliferation, differentiation, apoptosis and stress response. Therefore, dysregulation, or improper functioning of these cascades, is involved in the induction and progression of diseases such as cancer, diabetes, autoimmune diseases, and developmental abnormalities. Many of these physiological, and pathological functions are mediated by MAPK-dependent transcription of various regulatory genes. In order to induce transcription and the consequent functions, the signals transmitted via the cascades need to enter the nucleus, where they may modulate the activity of transcription factors and chromatin remodeling enzymes. In this review, we briefly cover the composition of the MAPK cascades, as well as their physiological and pathological functions. We describe, in more detail, many of the important nuclear activities of the MAPK cascades, and we elaborate on the mechanisms of ERK1/2 translocation into the nucleus, including the identification of their nuclear translocation sequence (NTS) binding to the shuttling protein importin7. Overall, the nuclear translocation of signaling components may emerge as an important regulatory layer in the induction of cellular processes, and therefore, may serve as targets for therapeutic intervention in signaling-related diseases such as cancer and diabetes. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.
    Biochimica et Biophysica Acta 12/2010; 1813(9):1619-33. DOI:10.1016/j.bbamcr.2010.12.012 · 4.66 Impact Factor
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    • "The expression of proinflammatory cytokines can be regulated at both the transcriptional and post-transcriptional levels (Kaminska, 2005; Clark et al., 2009). MAP kinases are key mediators of eukaryotic transcriptional responses to extracellular signals and control gene expression via the phosphorylation and regulation of transcription factors, coregulatory proteins and chromatin proteins (Whitmarsh, 2007). "
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    ABSTRACT: A majority, if not all, acute and progressive neurodegenerative diseases are accompanied by local microglia-mediated inflammation, astrogliosis, infiltration of immune cells, and activation of the adaptive immunity. These processes progress by the expression of cytokines, adhesion molecules, proteases, and other inflammation mediators. In response to brain injury or infection, intracellular signaling pathways are activated in microglia, which turn on inflammatory and antigen-presenting cell functions. Different extrinsic signals shape microglial activation toward neuroprotective or neurotoxic phenotype under pathological conditions. This review discusses recent advances regarding molecular mechanisms of inflammatory signal transduction in neurological disorders and in in vitro models of inflammation/gliosis. Mitogen-activated protein kinases (MAPKs) are a family of serine/threonine protein kinases responsible for most cellular responses to cytokines and external stress signals and crucial for regulation of the production of inflammation mediators. Increased activity of MAPKs in activated microglia and astrocytes, and their regulatory role in the synthesis of inflammatory cytokines mediators, make them potential targets for novel therapeutics. MAPK inhibitors emerge as attractive anti-inflammatory drugs, because they are capable of reducing both the synthesis of inflammation mediators at multiple levels and are effective in blocking inflammatory cytokine signaling. Small molecule inhibitors targeting of p38 MAPK and JNK pathways have been developed and offer a great potential as potent modulators of brain inflammation and gliosis in neurological disorders, where cytokine overproduction contributes to disease progression. Many of the pharmacological MAPK inhibitors can be administered orally and initial results show therapeutic benefits in preclinical animal models.
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