Article

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: 3.52). 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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    • "It has been reported that adenosine-uracil multimers known as AU-rich element (ARE) in the 3′-untranslated region (3′-UTR) plays an important role in the post-transcriptional regulation of TNF-α mRNA [13] [14]. The regulation of mRNA stability is mediated by ARE-binding proteins, which interact with ARE and promote/suppress mRNA decay [15] [16] [17]. "
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    • "The analysis of LPS-induced changes in macrophage gene expression profiles revealed genome-wide alterations in alveolar and RAW 264.7 macrophages (Rutledge et al. 2011;Reynier et al. 2012), but information about the contribution of post-transcriptional processes that affect expression downstream from differential gene regulation is still fragmentary. Many cytokine mRNAs, which have very short half-lives, bear AU-rich sequence elements (ARE) within their 3 ′ UTRs (Wilusz et al. 2001) that represent specific protein interaction sites (Anderson 2008;Clark et al. 2009). It has been shown that the LPS-dependent MKK3/6-p38-MK2 pathway increases the TNF-α mRNA half-life through phosphorylation and stabilization of the ARE-binding protein tristetraprolin (TTP) (Hitti et al. 2006;Tiedje et al. 2010Tiedje et al. , 2012); similarly KH-type splicing regulatory protein (KSRP) stabilizes IL-8 mRNA (Winzen et al. 2007). "
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    ABSTRACT: Macrophage activation by bacterial lipopolysaccharides (LPS) is induced through Toll-like receptor 4 (TLR4). The synthesis and activity of TLR4 downstream signaling molecules modulates the expression of pro- and anti-inflammatory cytokines. To address the impact of post-transcriptional regulation on that process, we performed RIP-Chip analysis. Differential association of mRNAs with heterogeneous nuclear ribonucleoprotein K (hnRNP K), an mRNA-specific translational regulator in differentiating hematopoietic cells, was studied in noninduced and LPS-activated macrophages. Analysis of interactions affected by LPS revealed several mRNAs encoding TLR4 downstream kinases and their modulators. We focused on transforming growth factor-β-activated kinase 1 (TAK1) a central player in TLR4 signaling. HnRNP K interacts specifically with a sequence in the TAK1 mRNA 3' UTR in vitro. Silencing of hnRNP K does not affect TAK1 mRNA synthesis or stability but enhances TAK1 mRNA translation, resulting in elevated TNF-α, IL-1β, and IL-10 mRNA expression. Our data suggest that the hnRNP K-3' UTR complex inhibits TAK1 mRNA translation in noninduced macrophages. LPS-dependent TLR4 activation abrogates translational repression and newly synthesized TAK1 boosts macrophage inflammatory response.
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    • "Only combined JNK1/2-deficient cells and not the single knockout cell, exhibit a severe defect in Tnfα mRNA expression [45, 47], suggesting redundant actions of JNK1 and JNK2 in TNF regulation. Although some reports suggest that JNK could also be involved in post-translational regulation of cytokines, direct mechanistic links between JNK and mRNA stability or translation remain elusive [48]. "
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