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: 20). 01/2006; 6(12):1280-7. DOI: 10.1038/ni1266
Source: PubMed


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, Oct 04, 2015
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    • "We observed that CX3CL1 protein levels were not correlated 1:1 with GM-CSF in human plasma. One possible reason for the lack of unity between the two proteins is GM-CSF mRNA is post-transcriptionally regulated and either rapidly degraded or stabilized depending on the stimulating factors [22], potentially decreasing translation of GM-CSF mRNA to protein. Interestingly, GM-CSF signaling significantly increases IL-1β secretion [23] and IL-1β is implicated in atherosclerosis in animal studies [24]. "
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    ABSTRACT: Background Fractalkine (CX3CL1) promotes migration and adhesion of lymphocytes and monocytes to inflamed tissues. Prior studies show a role for CX3CL1 in atherosclerosis. The relationship between inflammatory cytokines, cholesterol, and CX3CL1 levels in human subjects without known coronary artery disease is not well characterized. The goal of our study was to assess baseline CX3CL1 levels, and after modulation of cholesterol levels by statins to determine if CX3CL1 is linked to cholesterol levels or inflammatory stimuli. Methods We performed a blinded, randomized hypothesis generating study in human subjects without known coronary artery disease treated sequentially with three statins of differing potencies. Fractalkine (CX3CL1), GM-CSF, VEGF-A, other chemokines, and lipid levels were measured. Mechanistic studies of CX3CL1 induction by LDL cholesterol and TNFα in cultured human endothelial cells were performed using real-time PCR. Results Therapy with statins reduced total and LDL cholesterol levels as expected. CX3CL1 levels were significantly reduced from no statin control levels (89.9 ± 18.5 pg/mL) after treatment with atorvastatin (60.0 ± 7.8 pg/mL), pravastatin (54.2 ± 7.0 pg/mL) and rosuvastatin (65.6 ± 7.3 pg/mL) (χ2(2) = 17.4, p ≤ 0.001). Cholesterol is not a known regulator of CX3CL1. We found GM-CSF (r2 = 0.524; p < 0.005) and VEGF-A (r2 = 0.4; p < 0.005) levels were highly and positively correlated with CX3CL1. Total (r2 = 0.086) and LDL cholesterol (r2 = 0.059) levels weakly correlated with CX3CL1 levels. Finally, we tested whether LDL cholesterol could induce CX3CL1, GM-CSF, and VEGF-A in human endothelial cells, versus TNFα. LDL cholesterol alone resulted in small, non-significant increases in CX3CL1 and GM-CSF, while TNFα resulted in > 10-fold induction. Conclusions Our findings suggest that while statins suppress CX3CL1 levels, inflammatory cytokines may be the major regulator of CX3CL1 levels rather than cholesterol itself. Additional studies in a larger patient population are needed to confirm these findings, determine if CX3CL1 levels reflect inflammation levels, and potentially add to standard risk factors in prediction of atherosclerotic disease events.
    Clinical and Translational Medicine 06/2014; 3:14. DOI:10.1186/2001-1326-3-14
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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 · 11.34 Impact Factor
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    • "This association was RNA-independent as addition of RNAseA did not disrupt the complex. AUF1 has already been shown to bind Pin1 to regulate the activity of the GM-CSF [35], [56] and Pth [36] mRNAs. However HuR has not been previously shown to bind Pin1. "
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    ABSTRACT: The peptidyl-prolyl isomerase Pin1 is over-expressed in several cancer tissues is a potential prognostic marker in prostate cancer, and Pin1 ablation can suppress tumorigenesis in breast and prostate cancers. Pin1 can co-operate with activated ErbB2 or Ras to enhance tumorigenesis. It does so by regulating the activity of proteins that are essential for gene expression and cell proliferation. Several targets of Pin1 such as c-Myc, the Androgen Receptor, Estrogen Receptor-alpha, Cyclin D1, Cyclin E, p53, RAF kinase and NCOA3 are deregulated in cancer. At the posttranscriptional level, emerging evidence indicates that Pin1 also regulates mRNA decay of histone mRNAs, GM-CSF, Pth, and TGFβ mRNAs by interacting with the histone mRNA specific protein SLBP, and the ARE-binding proteins AUF1 and KSRP, respectively. To understand how Pin1 may affect mRNA abundance on a genome-wide scale in mammalian cells, we used RNAi along with DNA microarrays to identify genes whose abundance is significantly altered in response to a Pin1 knockdown. Functional scoring of differentially expressed genes showed that Pin1 gene targets control cell adhesion, leukocyte migration, the phosphatidylinositol signaling system and DNA replication. Several mRNAs whose abundance was significantly altered by Pin1 knockdown contained AU-rich element (ARE) sequences in their 3' untranslated regions. We identified HuR and AUF1 as Pin1 interacting ARE-binding proteins in vivo. Pin1 was also found to stabilize all core histone mRNAs in this study, thereby validating our results from a previously published study. Statistical analysis suggests that Pin1 may target the decay of essential mRNAs that are inherently unstable and have short to medium half-lives. Thus, this study shows that an important biological role of Pin1 is to regulate mRNA abundance and stability by interacting with specific RNA-binding proteins that may play a role in cancer progression.
    PLoS ONE 01/2014; 9(1):e85427. DOI:10.1371/journal.pone.0085427 · 3.23 Impact Factor
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