Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

mRNA stability is a major determinant of inflammatory gene expression. Rapid degradation of interleukin-8 (IL-8) mRNA is imposed by a bipartite AU-rich element (ARE) in the 3' untranslated region (R. Winzen et al., Mol. Cell. Biol. 24:4835-4847, 2004). Small interfering RNA-mediated knockdown of the ARE-binding protein KSRP resulted in stabilization of IL-8 mRNA or of a beta-globin reporter mRNA containing the IL-8 ARE. Rapid deadenylation was impaired, indicating a crucial role for KSRP in this step of mRNA degradation. The two IL-8 ARE domains both contribute to interaction with KSRP, corresponding to the importance of both domains for rapid degradation. Exposure to the inflammatory cytokine IL-1 has been shown to stabilize IL-8 mRNA through p38 mitogen-activated protein (MAP) kinase and MK2. IL-1 treatment impaired the interaction of KSRP with the IL-8 ARE in a manner dependent on p38 MAP kinase but apparently independent of MK2. Instead, evidence that TTP, a target of MK2, can also destabilize the IL-8 ARE reporter mRNA is presented. In a comprehensive approach to identify mRNAs controlled by KSRP, two criteria were evaluated by microarray analysis of (i) association of mRNAs with KSRP in pulldown assays and (ii) increased amounts in KSRP knockdown cells. According to both criteria, a group of 100 mRNAs is controlled by KSRP, many of which are unstable and encode proteins involved in inflammation. These results indicate that KSRP functions as a limiting factor in inflammatory gene expression.
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PMID:Functional analysis of KSRP interaction with the AU-rich element of interleukin-8 and identification of inflammatory mRNA targets. 1790 89

Extracellular-regulated kinases and p38 mitogen-activated protein kinases are activated in innate (and adaptive) immunity and signal via different routes to alter the stability and translation of various cytokine mRNAs, enabling immune cells to respond promptly. This regulation involves mRNA elements, such as AU-rich motifs, and mRNA-binding proteins, such as tristetraprolin (TTP), HuR, and hnRNPK-homology (KH) type splicing regulatory protein (KSRP). Signal-dependent phosphorylation of mRNA-binding proteins often alters their subcellular localization or RNA-binding affinity. Furthermore, it could lead to an altered interaction with other mRNA-binding proteins and altered scaffolding properties for mRNA-modifying enzymes, such as deadenylases, polyadenylases, decapping enzymes, poly(A) binding proteins, exo- or endonucleases, and proteins of the exosome machinery. In many cases, this results in unstable mRNAs being stabilized, with their translational arrest being released and cytokine production being stimulated. Hence, components of these mechanisms are potential targets for the modulation of the inflammatory response.
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PMID:The role of mammalian MAPK signaling in regulation of cytokine mRNA stability and translation. 2469