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Shen, Z. J., Esnault, S. & Malter, J. S. The peptidyl-prolyl isomerase Pin1 regulates the stability of granulocyte-macrophage colony-stimulating factor mRNA in activated eosinophils. Nat. Immunol. 6, 1280-1287

The Waisman Center for Developmental Disabilities, the Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine, Madison, Wisconsin 53705, USA.
Nature Immunology (Impact Factor: 24.97). 01/2006; 6(12):1280-7. DOI: 10.1038/ni1266
Source: PubMed

ABSTRACT The infiltration, accumulation and degranulation of eosinophils in the lung represents a hallmark of active asthma. In vivo or in vitro eosinophil activation triggers the secretion of the antiapoptotic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). We now identify Pin1, a cis-trans isomerase, as an essential component of the ribonucleoprotein complex responsible for GM-CSF mRNA stabilization, cytokine secretion and the survival of activated eosinophils. Pin1 regulated the association of the AU-rich element-binding proteins AUF1 and hnRNP C with GM-CSF mRNA, accelerating or slowing decay, respectively. These data indicate Pin1 is a key mediator of GM-CSF production.

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Available from: James S Malter, Aug 25, 2015
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    • "Moreover, the elevated expression of a-SMA and Pin1 in fibrotic liver tissues was abolished by juglone treatment (Fig. 1D), which supports the notion that HSC activation may be controlled by Pin1. It has been reported that juglone causes proteasome-dependent Pin1 degradation as well as inactivation of Pin1 enzyme activity [9] [10]. Further , we used LX-2 human immortalised stellate cells to determine whether Pin1 acts directly on stellate cells. "
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    ABSTRACT: Background/Aims Therapeutic management of liver fibrosis remains an unsolved clinical problem. Hepatic accumulation of extracellular matrix, mainly collagen, is mediated by the production of transforming growth factor-β1 (TGFβ1) in stellate cells. Pin1, a peptidyl–prolyl isomerase, plays an important pathophysiological role in several diseases, including neurodegeneration and cancer. Herein, we determined whether Pin1 regulates liver fibrogenesis and examined its mechanism of action by focusing on TGFβ1 signalling and hepatic stellate cell (HSC) activation. Methods Pin1 expression was assessed by immunohistochemistry, Western blot or real-time-polymerase chain reaction (RT-PCR) analyses of human and mouse fibrotic liver samples. The role of Pin1 during HSC activation was estimated using Pin1-null mouse embryonic fibroblast (MEF) cells and Pin1-overexpressing LX-2 human hepatic stellate cells. Results Pin1 expression was elevated in human and mouse fibrotic liver tissues, and Pin1 inhibition improved dimethylnitrosamine (DMN)-induced liver fibrosis in mice. Pin1 inhibition reduced the mRNA or protein expression of TGFβ1 and α-smooth muscle actin (α-SMA) by DMN treatment. Pin1 knockdown suppressed TGFβ1 gene expression in both LX-2 and MEF cells. Pin1-mediated TGFβ1 gene transcription was controlled by extracellular signal-regulated kinase (ERK)- and phosphoinositide 3-kinase/Akt-mediated activator protein-1 (AP-1) activation. Moreover, TGFβ1-stimulated Smad2/3 phosphorylation and plasminogen activator inhibitor-1 expression were inhibited by Pin1 knockdown. Conclusions Pin1 induction during liver fibrosis is involved in hepatic stellate cell activation, TGFβ1 expression, and TGFβ1-mediated fibrogenesis signalling.
    Journal of Hepatology 06/2014; 60(6). DOI:10.1016/j.jhep.2014.02.004 · 10.40 Impact Factor
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    • "The extent of the GM-CSF produced by the T cells is controlled posttranslationally, by a mechanism [65] involving the adenylate-uridylate-rich elements (AU-rich elements; AREs) in the 3' untranslated region (UTR) of the gene, which determine the stability of the transcribed mRNA [66]. Shen et al., have used an in vitro system in which the GM-CSF-dependent survival of eosinophils increases in the presence of hyaluronic acid that promotes GM-CSF production [46]. In these studies, Pin1 was found to regulate the association of two ARE-binding proteins, AU-rich element RNA-binding protein 1 (AUF1) and heterogeneous nuclear ribonucleoproteins C (hnRNPC), with GM-CSF mRNA. "
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    ABSTRACT: Pin1 is a peptidyl-prolyl isomerase (PPIase) that catalyzes the conversion of specific Pro-directed Ser/Thr phosphorylation motifs between the cis and trans conformations. It has been implicated in multiple aspects of cell cycle regulation and neural differentiation. In addition, Pin1 is involved in cellular processes related to a number of human pathologies, including cancer and Alzheimer's disease. More recent studies provided evidence for the participation of Pin1 in the regulation of immune cell functions and immune responses, independent of the activity of the related PPIases, cyclophilin A and FKBP, also known as immunophilins. In this review we focus on the role of Pin1 in the regulation of innate and adaptive immune system cell functions. Pin1 mediated isomerization of phosphoproteins represents a unique signaling mechanism that regulates normal immune functions and contributes to the development of immunopathologies. It can therefore serve as a useful diagnostic tool and a potential therapeutic target.
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    • "Hyperphosphorylation of AUF1 correlated with increased stability of mRNAs encoding numerous cyclins and the MYC oncoprotein. Likewise, phosphorylation of AUF1 during eosinophil activation stabilizes GM-CSF mRNA (Shen et al., 2005). In this case, phosphorylation leads to cis-trans isomerization of serine-proline and serine-threonine peptide bonds by the peptidyl-prolyl isomerase Pin1, thereby lowering association of AUF1 with the ARE and stabilizing the mRNA. "
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    ABSTRACT: Messenger RNA decay is an essential step in gene expression to set mRNA abundance in the cytoplasm. The binding of proteins and/or noncoding RNAs to specific recognition sequences or secondary structures within mRNAs dictates mRNA decay rates by recruiting specific enzyme complexes that perform the destruction processes. Often, the cell coordinates the degradation or stabilization of functional subsets of mRNAs encoding proteins collectively required for a biological process. As well, extrinsic or intrinsic stimuli activate signal transduction pathways that modify the mRNA decay machinery with consequent effects on decay rates and mRNA abundance. This review is an update to our 2001 Gene review on mRNA stability in mammalian cells, and we survey the enormous progress made over the past decade.
    Gene 03/2012; 500(1):10-21. DOI:10.1016/j.gene.2012.03.021 · 2.08 Impact Factor
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