The peptidyl-prolyl isomerase Pin1 facilitates cytokine-induced survival of eosinophils by suppressing Bax activation

Waisman Center for Developmental Disabilities, the Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA.
Nature Immunology (Impact Factor: 20). 03/2009; 10(3):257-65. DOI: 10.1038/ni.1697
Source: PubMed


The mechanisms by which cytokine signals prevent the activation and mitochondrial targeting of the proapoptotic protein Bax are unclear. Here we show, using primary human eosinophils, that in the absence of the prosurvival cytokines granulocyte-macrophage colony-stimulating factor and interleukin 5, Bax spontaneously underwent activation and initiated mitochondrial disruption. Inhibition of Bax resulted in less eosinophil apoptosis, even in the absence of cytokines. Granulocyte-macrophage colony-stimulating factor induced activation of the kinase Erk1/2, which phosphorylated Thr167 of Bax; this facilitated new interaction of Bax with the prolyl isomerase Pin1. Blockade of Pin1 led to cleavage and mitochondrial translocation of Bax and caspase activation, regardless of the presence of cytokines. Our findings indicate that Pin1 is a key mediator of prosurvival signaling and is a regulator of Bax function.

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    • "The results of our cellular experiments with CHX, which inhibits contributions to apoptosis from transcriptionally driven protein synthesis, synthetic p53-derived peptides, which lack transcriptional effects, and silencing of relevant genes, support a mechanistic model in which Pin1-induced isomerization of Pro 47 mediates cytosolic p53-dependent BAX activation and apoptosis. Pin1 was reported to inhibit BAX activation in eosinophyles after phosphorylation of BAX Thr 167 (preceding Pro 168 ) by Erk1/2, as a consequence of cytokine signaling (Shen et al., 2009). To determine the potential contributions of Pin1 to both proapoptotic or pro-survival signaling in H1299 p53-ER Tam cells, we interrogated the status of Erk1/2 activation and BAX Thr 167 phosphorylation. "
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    ABSTRACT: The cytosolic fraction of the tumor suppressor p53 activates the apoptotic effector protein BAX to trigger apoptosis. Here we report that p53 activates BAX through a mechanism different from that associated with activation by BH3 only proteins (BIM and BID). We observed that cis-trans isomerization of proline 47 (Pro47) within p53, an inherently rare molecular event, was required for BAX activation. The prolyl isomerase Pin1 enhanced p53-dependent BAX activation by catalyzing cis-trans interconversion of p53 Pro47. Our results reveal a signaling mechanism whereby proline cis-trans isomerization in one protein triggers conformational and functional changes in a downstream signaling partner. Activation of BAX through the concerted action of cytosolic p53 and Pin1 may integrate cell stress signals to induce a direct apoptotic response. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 07/2015; 59(4). DOI:10.1016/j.molcel.2015.06.029 · 14.02 Impact Factor
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    • "Comprehensive studies by Malter and colleague demonstrated that Pin1 serves as a regulator of expression of several types of cytokines and chemokines in different populations of immunocytes [4] [46] [59] [60] [61]. The first cytokine, whose production was reported to be regulated by Pin1, is the granulocyte-macrophage colony-stimulating factor (GM-CSF). "
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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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    • "As reported, treatment of HK-2 cells with high glucose and angiotensin II increased the protein–protein association between p-p66Shc and Pin1 in the cytosol, and with cytochrome c in the mitochondria [38]. A recent report demonstrated that blockade of Pin1 led to cleavage and mitochondrial translocation of Bax and caspase activation [39]. In aggregate, our present data suggested that Pin1 regulated cell proliferation by enhancing the resistance to apoptosis through dysfunction of the Bax/Bcl-2/cytochrome c/caspases-9 and -3 signalling pathway. "
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    ABSTRACT: Type 2 diabetes (T2D) is associated with accelerated restenosis rates after angioplasty. We have previously proved that Pin1 played an important role in vascular smooth muscle cell (VSMC) cycle and apoptosis. But neither the role of Pin1 in restenosis by T2D, nor the molecular mechanism of Pin1 in these processes has been elucidated. A mouse model of T2D was generated by the combination of high-fat diet (HFD) and streptozotocin (STZ) injections. Both Immunohistochemistry and Western blot revealed that Pin1 expression was up-regulated in the arterial wall in T2D mice and in VSMCs in culture conditions mimicking T2D. Next, increased activity of Pin1 was observed in neointimal hyperplasia after arterial injury in T2D mice. Further analysis confirmed that 10% serum of T2D mice and Pin1-forced expression stimulated proliferation, inhibited apoptosis, enhanced cell cycle progression and migration of VSMCs, whereas Pin1 knockdown resulted in the converse effects. We demonstrated that STAT3 signalling and mitochondria-dependent pathways played critical roles in the involvement of Pin1 in cell cycle regulation and apoptosis of VSMCs in T2D. In addition, VEGF expression was stimulated by Pin1, which unveiled part of the mechanism of Pin1 in regulating VSMC migration in T2D. Finally, the administration of juglone via pluronic gel onto injured common femoral artery resulted in a significant inhibition of the neointima/media ratio. Our findings demonstrated the vital effect of Pin1 on the VSMC proliferation, cell cycle progression, apoptosis and migration that underlie neointima formation in T2D and implicated Pin1 as a potential therapeutic target to prevent restenosis in T2D.
    Journal of Cellular and Molecular Medicine 06/2013; 17(8). DOI:10.1111/jcmm.12082 · 4.01 Impact Factor
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