p38 mitogen-activated protein kinase (MAPK) is activated by inflammatory stimuli such as bacterial lipopolysaccharide (LPS), interleukin-1, and tumor necrosis factor. We have previously shown that the pyridinyl imidazole SB 203580, which inhibits it, blocks interleukin-1 induction of cyclooxygenase-2 (COX-2) matrix metalloproteinase 1 3 mRNAs in fibroblasts. Here we explore role MAPK response human monocytes to LPS. 0.1 microM 203580 significantly inhibited LPS COX-2 factor mRNAs. The...

Signal transduction pathways regulate gene expression in part by modulating the stability of specific mRNAs. For example, mitogen-activated protein kinase (MAPK) p38 pathway mediates stabilization tumor necrosis factor alpha (TNF-alpha) mRNA myeloid cells stimulated with bacterial lipopolysaccharide (LPS). The zinc finger tristetraprolin (TTP) is expressed response to LPS and regulates TNF-alpha mRNA. We show that stimulation RAW264.7 mouse macrophages induces binding TTP 3' untranslated...

The mitogen-activated protein kinase (MAPK) p38/MAPK-activated 2 (MK2) signaling pathway plays an important role in the posttranscriptional regulation of tumor necrosis factor (TNF), which is dependent on adenine/uridine-rich element (ARE) 3′ untranslated region TNF mRNA. After lipopolysaccharide (LPS) stimulation, MK2-deficient macrophages show a 90% reduction production compared to wild type. Tristetraprolin (TTP), induced by LPS, binds ARE and destabilizes Accordingly, lacking TTP produce...

The stability of cyclooxygenase 2 (Cox-2) mRNA is regulated positively by proinflammatory stimuli acting through mitogen-activated protein kinase (MAPK) p38 and negatively anti-inflammatory glucocorticoids such as dexamethasone. A tetracycline-regulated reporter system was used to investigate mechanisms regulation Cox-2 stability. Dexamethasone found destabilize beta-globin-Cox-2 mRNAs inhibiting p38. This inhibition occurred at the level itself: stabilization a upstream blocked...

The p38 mitogen-activated protein kinase (MAPK) signaling pathway, acting through the downstream MK2, regulates stability of many proinflammatory mRNAs that contain adenosine/uridine-rich elements (AREs). It is thought to do this by modulating expression or activity ARE-binding proteins regulate mRNA turnover. MK2 phosphorylates and mRNA-destabilizing tristetraprolin (TTP) at serines 52 178. Here we show MAPK pathway subcellular localization TTP protein. A inhibitor causes rapid...

The translation of tumour necrosis factor alpha (TNFalpha) mRNA is regulated by the stress-activated protein kinase p38, which also controls stability several pro-inflammatory mRNAs. regulation TNFalpha gene expression in a mouse macrophage cell line RAW264.7 was re-examined using an inhibitor kinases. Stimulation these cells with bacterial lipopolysaccharide resulted stabilisation mRNA, reversed specific inhibition p38. An adenosine/uridine-rich element from 3' untranslated region conferred...

The mechanism by which p38 mitogen‐activated protein kinase (MAPK) regulates the induction of cyclooxygenase (COX)‐2 interleukin‐1 (IL‐1) has been investigated in HeLa cells. SB 203580, an inhibitor MAPK, range 0.1–1 μM inhibited IL‐1‐stimulated PGE 2 (but not arachidonic acid) release and this was associated with inhibition COX‐2 mRNA. IL‐1 stimulated transcription cells about 2‐fold as judged both reporter gene nuclear run‐on assays. had no significant effect on this. However, previously...

Tristetraprolin (TTP) is an mRNA-destabilizing protein that negatively regulates the expression of proinflammatory mediators such as tumor necrosis factor α, granulocyte/macrophage colony-stimulating factor, and cyclooxygenase 2. Here we investigate regulation TTP in mouse macrophage cell line RAW264.7. We show mRNA expressed a biphasic manner following stimulation cells with lipopolysaccharide second phase expression, like first, dependent on mitogen-activated kinase (MAPK) p38. MAPK p38...

Significance Neutrophils are the major effectors of acute inflammation responding to tissue injury or infection. The clearance apoptotic neutrophils by inflammatory macrophages also provides a powerful proresolution signal. Apoptotic necrotic release abundant amounts antimicrobial peptides alpha defensins. In this report, we show that most these peptides, HNP1 (Human Neutrophil Peptide 1), profoundly inhibits protein translation. It achieves without affecting mRNA stability preventing...

Translational control of many mRNAs in developing metazoan embryos is achieved by alterations their poly(A) tail length. A family cytoplasmic poly(A)-binding proteins (PABPs) bind the and can regulate mRNA translation stability. However, despite extensive biochemical characterization one member (PABP1), surprisingly little known about vivo roles or functional relatedness. Because no information available vertebrates, we address biological roles, establishing that each PABPs conserved Xenopus...

ABSTRACT Infection of cells by herpes simplex virus type 1 (HSV-1) triggers host cell shutoff whereby mRNAs are degraded and cellular protein synthesis is diminished. However, translation continues because the translational apparatus in HSV-infected maintained an active state. Surprisingly, poly(A)-binding (PABP1), a predominantly cytoplasmic that required for efficient initiation, partially relocated to nucleus during HSV-1 infection. This relocalization occurred time-dependent manner with...

DAZ-associated protein 1 (DAZAP1) is an RNA-binding required for normal growth, development, and fertility in mice. However, its molecular functions have not been elucidated. Here we find that Xenopus laevis human DAZAP1, which are each expressed as short long forms, act mRNA-specific activators of translation a manner sensitive to the number binding sites present within 3' UTR. Domain mapping suggests this conserved function mainly associated with C-terminal regions DAZAP1. Interestingly,...

PABP1 [poly(A)-binding protein 1] is a central regulator of mRNA translation and stability required for miRNA (microRNA)-mediated regulation nonsense-mediated decay. Numerous protein, as well RNA, interactions underlie its multi-functional nature; however, it unclear how different activities are co-ordinated, since many partners interact via overlapping binding sites. In the present study, we show that human subject to elaborate post-translational modification, identifying 14 modifications...

Background Thymocyte expressed molecule involved in selection 1 (Themis1, SwissProt accession number Q8BGW0) is the recently characterised founder member of a novel family proteins. A second this family, Themis2 (Q91YX0), also known as ICB1 (Induced on contact with basement membrane 1), remains unreported at protein level despite microarray and EST databases reporting mRNA expression B cells macrophages. Methodology/Principal Findings Here we characterise for first time show that it acts...

Oocyte maturation and early embryonic development require the cytoplasmic polyadenylation concomitant translational activation of stored maternal mRNAs. ePAB [embryonic poly(A)-binding protein, also known as ePABP PABPc1-like] is a multifunctional post-transcriptional regulator that binds to poly(A) tails. In present study we find dynamically modified phosphoprotein in Xenopus laevis oocytes show by mutation phosphorylation at four residue cluster required for oocyte maturation. We further...

Once an mRNA is synthesized and processed, the immediate translation later destruction of transcript not as inevitable central molecular biology dogma suggests. Interest in field post-transcriptional control continues to grow rapidly, regulation these multiple steps gene expression implicated diverse aspects such metabolism, neurology, reproduction viral lifecycle regulation. Researchers who utilize various combinations human studies, animal models, cellular, genetic, biochemical techniques...