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Xiao Zhen Zhou - One of the best experts on this subject based on the ideXlab platform.

  • inactivation of the prolyl isomerase PIN1 sensitizes brca1 proficient breast cancer to parp inhibition
    Cancer Research, 2020
    Co-Authors: Man Li Luo, Chunhau Chen, Fang Zheng, Wenying Chen, Zhimei Liang, Gurushankar Chandramouly, Jianan Tan, Nicholas A Willis, Mateus De Oliveira Taveira, Xiao Zhen Zhou
    Abstract:

    PARP inhibitor monotherapies are effective to treat patients with breast, ovary, prostate, and pancreatic cancer with BRCA1 mutations, but not to the much more frequent BRCA wild-type cancers. Searching for strategies that would extend the use of PARP inhibitors to BRCA1-proficient tumors, we found that the stability of BRCA1 protein following ionizing radiation (IR) is maintained by postphosphorylational prolyl-isomerization adjacent to Ser1191 of BRCA1, catalyzed by prolyl-isomerase PIN1. Extinction of PIN1 decreased homologous recombination (HR) to the level of BRCA1-deficient cells. PIN1 stabilizes BRCA1 by preventing ubiquitination of Lys1037 of BRCA1. Loss of PIN1, or introduction of a BRCA1-mutant refractory to PIN1 binding, decreased the ability of BRCA1 to localize to repair foci and augmented IR-induced DNA damage. In vitro growth of HR-proficient breast, prostate, and pancreatic cancer cells were modestly repressed by olaparib or PIN1 inhibition using all-trans retinoic acid (ATRA), while combination treatment resulted in near-complete block of cell proliferation. In MDA-MB-231 xenografts and triple-negative breast cancer patient-derived xenografts, either loss of PIN1 or ATRA treatment reduced BRCA1 expression and sensitized breast tumors to olaparib. Together, our study reveals that PIN1 inhibition, with clinical widely used ATRA, acts as an effective HR disrupter that sensitizes BRCA1-proficient tumors to PARP inhibition. SIGNIFICANCE: PARP inhibitors have been limited to treat homologous recombination-deficient tumors. All-trans retinoic acid, by inhibiting PIN1 and destabilizing BRCA1, extends benefit of PARP inhibitors to patients with homologous recombination-proficient tumors.See related commentary by Cai, p. 2977.

  • prolyl isomerase PIN1 regulates axon guidance by stabilizing crmp2a selectively in distal axons
    Cell Reports, 2015
    Co-Authors: Martin Balastik, Xiao Zhen Zhou, Meritxell Alberichjorda, Romana Weissova, Jakub žiak, Maria F Pazyramurphy, Katharina E Cosker, Olga Machonova, Iryna Kozmikova, Chunhau Chen
    Abstract:

    Axon guidance relies on precise translation of extracellular signal gradients into local changes in cytoskeletal dynamics, but the molecular mechanisms regulating dose-dependent responses of growth cones are still poorly understood. Here, we show that during embryonic development in growing axons, a low level of Semaphorin3A stimulation is buffered by the prolyl isomerase PIN1. We demonstrate that PIN1 stabilizes CDK5-phosphorylated CRMP2A, the major isoform of CRMP2 in distal axons. Consequently, PIN1 knockdown or knockout reduces CRMP2A levels specifically in distal axons and inhibits axon growth, which can be fully rescued by PIN1 or CRMP2A expression. Moreover, PIN1 knockdown or knockout increases sensitivity to Sema3A-induced growth cone collapse in vitro and in vivo, leading to developmental abnormalities in axon guidance. These results identify an important isoform-specific function and regulation of CRMP2A in controlling axon growth and uncover PIN1-catalyzed prolyl isomerization as a regulatory mechanism in axon guidance.

  • PIN1 dysregulation helps to explain the inverse association between cancer and alzheimer s disease
    Biochimica et Biophysica Acta, 2015
    Co-Authors: Jane A Driver, Xiao Zhen Zhou
    Abstract:

    Abstract Background PIN1 is an intracellular signaling molecule which plays a critical but opposite role in the pathogenesis of Alzheimer's disease (AD) and many human cancers. Scope of review We review the structure and function of the PIN1 enzyme, the diverse roles it plays in cycling cells and neurons, the epidemiologic evidence for the inverse association between cancer and AD, and the potential therapeutic implications of PIN1-based therapies. Major conclusions PIN1 is a unique enzyme that has effects on the function of target proteins by “twisting” them into different shapes. Cycling cells use PIN1 to help coordinate cell division. It is over-expressed and/or activated by multiple mechanisms in many common human cancers, and acts on multiple signal pathways to promote tumorigenesis. Inhibition of PIN1 in animal models has profound anti-tumor effects. In contrast, PIN1 is down-regulated or inactivated by multiple mechanisms in AD brains. The absence of PIN1 impairs tau function and amyloid precursor protein processing, leading to tangle- and amyloid-related pathologies and neurodegeneration in an age-dependent manner, resembling human AD. We have developed cis and trans conformation-specific antibodies to provide the first direct evidence that tau exists in distinct cis and trans conformations and that PIN1 accelerates its cis to trans conversion, thereby protecting against tangle formation in AD. General significance Available studies on PIN1 suggest that cancer and AD may share biological pathways that are deregulated in different directions. PIN1 biology opens exciting preventive and therapeutic horizons for both cancer and neurodegeneration. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.

  • regulation of phosphatidylinositol 5 phosphate signaling by PIN1 determines sensitivity to oxidative stress
    Science Signaling, 2012
    Co-Authors: Willemjan Keune, Xiao Zhen Zhou, David R Jones, Yvette Bultsma, Lilly Sommer, Nullin Divecha
    Abstract:

    Oxidative signaling and oxidative stress contribute to aging, cancer, and diseases resulting from neurodegeneration. PIN1 is a proline isomerase that recognizes phosphorylated substrates and regulates the localization and conformation of its targets. PIN1(-/-) mice show phenotypes associated with premature aging, yet mouse embryonic fibroblasts (MEFs) from these mice are resistant to hydrogen peroxide (H(2)O(2))-induced cell death. We found that the abundance of phosphatidylinositol-5-phosphate (PtdIns5P) was increased in response to H(2)O(2), an effect that was enhanced in PIN1(-/-) MEFs. Reduction of H(2)O(2)-induced PtdIns5P compromised cell viability in response to oxidative stress, suggesting that PtdIns5P contributed to the enhanced cell viability of PIN1(-/-) MEFs exposed to oxidative stress. The increased PtdIns5P in the PIN1(-/-) MEFs stimulated the expression of genes involved in defense against oxidative stress and reduced the accumulation of reactive oxygen species. PIN1 and PtdIns5P 4-kinases (PIP4Ks), enzymes that phosphorylate and thereby reduce the amount of PtdIns5P, interacted in a manner dependent on the phosphorylation of PIP4K. Although reintroduction of PIN1 into the PIN1(-/-) MEFs reduced the amount of PtdIns5P produced in response to H(2)O(2), in vitro assays indicated that the isomerase activity of PIN1 inhibited PIP4K activity. Whether this isomerise-mediated inhibition of PIP4K occurs in cells remains an open question, but the data suggest that the regulation of PIP4K by PIN1 may be complex.

  • Death-Associated Protein Kinase 1 Phosphorylates PIN1 and Inhibits Its Prolyl Isomerase Activity and Cellular Function
    Molecular cell, 2011
    Co-Authors: Tae Ho Lee, Chunhau Chen, Futoshi Suizu, Pengyu Huang, Cordelia Schiene-fischer, Sebastian Daum, Yan Jessie Zhang, Alison Goate, Ruey-hwa Chen, Xiao Zhen Zhou
    Abstract:

    PIN1 is a phospho-specific prolyl isomerase that regulates numerous key signaling molecules and whose deregulation contributes to disease notably cancer. However, since prolyl isomerases are often believed to be constitutively active, little is known whether and how PIN1 catalytic activity is regulated. Here, we identify death-associated protein kinase 1 (DAPK1), a known tumor suppressor, as a kinase responsible for phosphorylation of PIN1 on Ser71 in the catalytic active site. Such phosphorylation fully inactivates PIN1 catalytic activity and inhibits its nuclear location. Moreover, DAPK1 inhibits the ability of PIN1 to induce centrosome amplification and cell transformation. Finally, PIN1 pSer71 levels are positively correlated with DAPK1 levels and negatively with centrosome amplification in human breast cancer. Thus, phosphorylation of PIN1 Ser71 by DAPK1 inhibits its catalytic activity and cellular function, providing strong evidence for an essential role of the PIN1 enzymatic activity for its cellular function.

Akihide Ryo - One of the best experts on this subject based on the ideXlab platform.

  • prolyl isomerase PIN1 regulates the stability of hepatitis b virus core protein
    Frontiers in Cell and Developmental Biology, 2020
    Co-Authors: Mayuko Nishi, Takaji Wakita, Kei Miyakawa, Satoko Matsunaga, Hajera Khatun, Yutaro Yamaoka, Koichi Watashi, Masaya Sugiyama, Hirokazu Kimura, Akihide Ryo
    Abstract:

    The dynamic interplay between virus and host proteins is critical for establishing efficient viral replication and virus-induced pathogenesis. Phosphorylation-dependent prolyl isomerization by PIN1 provides a unique mechanism of molecular switching to control both protein function and stability. We demonstrate here that PIN1 binds and stabilizes hepatitis B virus core protein (HBc) in a phosphorylation-dependent manner, and promotes the efficient viral propagation. Phos-tag gel electrophoresis with various site-directed mutants of HBc revealed that Thr160 and Ser162 residues within the C terminal arginine-rich domain are phosphorylated concomitantly. GST pull-down assay and co-immunoprecipitation analysis demonstrated that PIN1 associated with phosphorylated HBc at the Thr160-Pro and Ser162-Pro motifs. Chemical or genetic inhibition of PIN1 significantly accelerated the rapid degradation of HBc via a lysosome-dependent pathway. Furthermore, we found that the pyruvate dehydrogenase phosphatase catalytic subunit 2 (PDP2) could dephosphorylate HBc at the PIN1-binding sites, thereby suppressing PIN1-mediated HBc stabilization. Our findings reveal an important regulatory mechanism of HBc stability catalyzed by PIN1 and may facilitate the development of new antiviral therapeutics targeting PIN1 function.

  • prolyl isomerase PIN1 regulates neuronal differentiation via β catenin
    Molecular and Cellular Biology, 2012
    Co-Authors: Kazuhiro Nakamura, Isao Kosugi, Daniel Y Lee, Angela Hafner, David A Sinclair, Akihide Ryo
    Abstract:

    The Wnt/β-catenin pathway promotes proliferation of neural progenitor cells (NPCs) at early stages and induces neuronal differentiation from NPCs at late stages, but the molecular mechanisms that control this stage-specific response are unclear. PIN1 is a prolyl isomerase that regulates cell signaling uniquely by controlling protein conformation after phosphorylation, but its role in neuronal differentiation is not known. Here we found that whereas PIN1 depletion suppresses neuronal differentiation, PIN1 overexpression enhances it, without any effects on gliogenesis from NPCs in vitro. Consequently, PIN1-null mice have significantly fewer upper layer neurons in the motor cortex and severely impaired motor activity during the neonatal stage. A proteomic approach identified β-catenin as a major substrate for PIN1 in NPCs, in which PIN1 stabilizes β-catenin. As a result, PIN1 knockout leads to reduced β-catenin during differentiation but not proliferation of NPCs in developing brains. Importantly, defective neuronal differentiation in PIN1 knockout NPCs is fully rescued in vitro by overexpression of β-catenin but not a β-catenin mutant that fails to act as a PIN1 substrate. These results show that PIN1 is a novel regulator of NPC differentiation by acting on β-catenin and provides a new postphosphorylation signaling mechanism to regulate developmental stage-specific functioning of β-catenin signaling in neuronal differentiation.

  • elevated PIN1 expression by c ebpalpha p30 blocks c ebpalpha induced granulocytic differentiation through c jun in aml
    Leukemia, 2010
    Co-Authors: John Anto Pulikkan, Akihide Ryo, V Dengler, A Peer A Zada, A Kawasaki, M Geletu, Z Pasalic, Stefan K Bohlander, Daniel G Tenen
    Abstract:

    The transcription factor CCAAT enhancer-binding protein alpha (C/EBPalpha) has an important role in granulopoiesis. The tumor suppressor function of C/EBPalpha is shown by the findings that loss of expression or function of C/EBPalpha in leukemic blasts contributes to a block in myeloid cell differentiation and to leukemia. C/EBPalpha mutations are found in around 9% of acute myeloid leukemia (AML) patients. The mechanism by which the mutant form of C/EBPalpha (C/EBPalpha-p30) exerts a differentiation block is not well understood. By using a proteomic screen, we have recently reported PIN1 as a target of C/EBPalpha-p30 in AML. In the present study, we show that C/EBPalpha-p30 induces PIN1 expression. We observed elevated PIN1 expression in leukemic patient samples. Induction of C/EBPalpha-p30 results in recruitment of E2F1 in the PIN1 promoter. We show that the inhibition of PIN1 leads to myeloid differentiation in primary AML blasts with C/EBPalpha mutations. Overexpression of PIN1 in myeloid cells leads to block of granulocyte differentiation. We also show that PIN1 increases the stability of the c-Jun protein by inhibiting c-Jun ubiquitination, and c-Jun blocks granulocyte differentiation mediated by C/EBPalpha. Our data suggest that the inhibition of PIN1 could be a potential strategy of treating AML patients with C/EBPalpha mutation.

  • PIN1 promotes transforming growth factor β induced migration and invasion
    Journal of Biological Chemistry, 2010
    Co-Authors: Isao Matsuura, Takafumi Uchida, Akihide Ryo, Keng Nan Chiang, Chen Yu Lai, Guannan Wang, Romila Ramkumar, Fang Liu
    Abstract:

    Transforming growth factor-β (TGF-β) regulates a wide variety of biological activities. It induces potent growth-inhibitory responses in normal cells but promotes migration and invasion of cancer cells. Smads mediate the TGF-β responses. TGF-β binding to the cell surface receptors leads to the phosphorylation of Smad2/3 in their C terminus as well as in the proline-rich linker region. The serine/threonine phosphorylation sites in the linker region are followed by the proline residue. PIN1, a peptidyl-prolyl cis/trans isomerase, recognizes phosphorylated serine/threonine-proline motifs. Here we show that Smad2/3 interacts with PIN1 in a TGF-β-dependent manner. We further show that the phosphorylated threonine 179-proline motif in the Smad3 linker region is the major binding site for PIN1. Although epidermal growth factor also induces phosphorylation of threonine 179 and other residues in the Smad3 linker region the same as TGF-β, PIN1 is unable to bind to the epidermal growth factor-stimulated Smad3. Further analysis suggests that phosphorylation of Smad3 in the C terminus is necessary for the interaction with PIN1. Depletion of PIN1 by small hairpin RNA does not significantly affect TGF-β-induced growth-inhibitory responses and a number of TGF-β/Smad target genes analyzed. In contrast, knockdown of PIN1 in human PC3 prostate cancer cells strongly inhibited TGF-β-mediated migration and invasion. Accordingly, TGF-β induction of N-cadherin, which plays an important role in migration and invasion, is markedly reduced when PIN1 is depleted in PC3 cells. Because PIN1 is overexpressed in many cancers, our findings highlight the importance of PIN1 in TGF-β-induced migration and invasion of cancer cells.

  • the prolyl isomerase PIN1 stabilizes the human t cell leukemia virus type 1 htlv 1 tax oncoprotein and promotes malignant transformation
    Biochemical and Biophysical Research Communications, 2009
    Co-Authors: Soojin Jeong, Akihide Ryo, Naoki Yamamoto
    Abstract:

    The HTLV Tax protein is crucial for viral replication and malignant transformation. We investigated the possible role of peptidyl prolyl isomerase PIN1 in the positive regulation of the human T-cell leukemia virus type 1 Tax. PIN1 is highly expressed in adult T-cell leukemia (ATL) cells expressing Tax protein and forced expression of PIN1 in turn increases the Tax protein expression. PIN1 prolonged the protein half-life of Tax by suppressing the ubiquitination and subsequent lysosomal degradation of Tax. PIN1 interacts with phosphorylated Tax on its Ser160-Pro motif at the mitotic phase. Finally, we found that PIN1 plays a supporting role in Tax-mediated cell transformation. Our current study demonstrates an important role for PIN1 in the post-translational regulation of Tax and suggests that the targeting of PIN1 may offer a new insight into the pathogenesis of HTLV-1 related diseases.

Gerburg M. Wulf - One of the best experts on this subject based on the ideXlab platform.

  • prolyl isomerase PIN1 acts downstream of mir200c to promote cancer stem like cell traits in breast cancer
    Cancer Research, 2014
    Co-Authors: Man Li Luo, Gerburg M. Wulf, Chunhau Chen, Daniel Y Lee, Pengyu Huang, Yandan Yao, Chang Gong, Wenjun Guo, Ferenc Reinhardt, Judy Lieberman
    Abstract:

    Breast cancer stem-like cells (BCSC) have been implicated in tumor growth, metastasis, drug resistance and relapse but druggable targets in appropriate subsets of this cell population have yet to be identified. Here we identify a fundamental role for the prolyl isomerase PIN1 in driving BCSC expansion, invasiveness and tumorigenicity, defining it as a key target of miR-200c which is known to be a critical regluator in BSCS. PIN1 overexpression expanded the growth and tumorigenicity of BCSC and triggered epithelial-mesenchymal transition (EMT). Conversely, genetic or pharmaacological inhibition of PIN1 reduced the abundance and self-renewal activity of BCSC. Moreover, moderate overexpression of miR-200c-resistant PIN1 rescued the BCSC defect in miR-200c-expressing cells. Genetic deletion of PIN1 also decreased the abundance and repopulating capability of normal mouse mammary stem cells. In human cells freshly isolated from reduction mammoplasty tissues, PIN1 overexpression endowed BCSC traits to normal breast epithelial cells, expanding both luminal and basal/myoepithelial lineages in these cells. In contrast, PIN1 silencing in primary breast cancer cells isolated from clinical samples inhibited the expansion, self-renewal activity and tumorigenesis of BCSC in vitro and in vivo. Overall, our work demonstrated that PIN1 is a pivotal regulator acting downstream of miR-200c to drive BCSC and breast tumorigenicity, highlighting a new therapeutic target to eradicate BCSC.

  • the prolyl isomerase PIN1 regulates amyloid precursor protein processing and amyloid β production
    Nature, 2006
    Co-Authors: Lucia Pastorino, Greg Finn, Xiao Zhen Zhou, Gerburg M. Wulf, Martin Balastik, Anyang Sun, Jormay Lim, Weiming Xia, Linda K Nicholson
    Abstract:

    Neuropathological hallmarks of Alzheimer's disease are neurofibrillary tangles composed of tau and neuritic plaques comprising amyloid-beta peptides (Abeta) derived from amyloid precursor protein (APP), but their exact relationship remains elusive. Phosphorylation of tau and APP on certain serine or threonine residues preceding proline affects tangle formation and Abeta production in vitro. Phosphorylated Ser/Thr-Pro motifs in peptides can exist in cis or trans conformations, the conversion of which is catalysed by the PIN1 prolyl isomerase. PIN1 has been proposed to regulate protein function by accelerating conformational changes, but such activity has never been visualized and the biological and pathological significance of PIN1 substrate conformations is unknown. Notably, PIN1 is downregulated and/or inhibited by oxidation in Alzheimer's disease neurons, PIN1 knockout causes tauopathy and neurodegeneration, and PIN1 promoter polymorphisms appear to associate with reduced PIN1 levels and increased risk for late-onset Alzheimer's disease. However, the role of PIN1 in APP processing and Abeta production is unknown. Here we show that PIN1 has profound effects on APP processing and Abeta production. We find that PIN1 binds to the phosphorylated Thr 668-Pro motif in APP and accelerates its isomerization by over 1,000-fold, regulating the APP intracellular domain between two conformations, as visualized by NMR. Whereas PIN1 overexpression reduces Abeta secretion from cell cultures, knockout of PIN1 increases its secretion. PIN1 knockout alone or in combination with overexpression of mutant APP in mice increases amyloidogenic APP processing and selectively elevates insoluble Abeta42 (a major toxic species) in brains in an age-dependent manner, with Abeta42 being prominently localized to multivesicular bodies of neurons, as shown in Alzheimer's disease before plaque pathology. Thus, PIN1-catalysed prolyl isomerization is a novel mechanism to regulate APP processing and Abeta production, and its deregulation may link both tangle and plaque pathologies. These findings provide new insight into the pathogenesis and treatment of Alzheimer's disease.

  • PIN1 regulates centrosome duplication and its overexpression induces centrosome amplification chromosome instability and oncogenesis
    Molecular and Cellular Biology, 2006
    Co-Authors: Futoshi Suizu, Gerburg M. Wulf, Kun Ping Lu
    Abstract:

    Phosphorylation on Ser/Thr-Pro motifs is a major mechanism regulating many events involved in cell proliferation and transformation, including centrosome duplication, whose defects have been implicated in oncogenesis. Certain phosphorylated Ser/Thr-Pro motifs can exist in two distinct conformations whose conversion in certain proteins is catalyzed specifically by the prolyl isomerase PIN1. PIN1 is prevalently overexpressed in human cancers and is important for the activation of multiple oncogenic pathways, and its deletion suppresses the ability of certain oncogenes to induce cancer in mice. However, little is known about the role of PIN1 in centrosome duplication and the significance of PIN1 overexpression in cancer development in vivo. Here we show that PIN1 overexpression correlates with centrosome amplification in human breast cancer tissues. Furthermore, PIN1 localizes to and copurifies with centrosomes in interphase but not mitotic cells. Moreover, PIN1 ablation in mouse embryonic fibroblasts drastically delays centrosome duplication without affecting DNA synthesis and PIN1 inhibition also suppresses centrosome amplification in S-arrested CHO cells. In contrast, overexpression of PIN1 drives centrosome duplication and accumulation, resulting in chromosome missegregation, aneuploidy, and transformation in nontransformed NIH 3T3 cells. More importantly, transgenic overexpression of PIN1 in mouse mammary glands also potently induces centrosome amplification, eventually leading to mammary hyperplasia and malignant mammary tumors with overamplified centrosomes. These results demonstrate for the first time that the phosphorylation-specific isomerase PIN1 regulates centrosome duplication and its deregulation can induce centrosome amplification, chromosome instability, and oncogenesis.

  • activation of β catenin signaling in prostate cancer by peptidyl prolyl isomerase PIN1 mediated abrogation of the androgen receptor β catenin interaction
    Molecular and Cellular Biology, 2006
    Co-Authors: Shaoyong Chen, Xiao Zhen Zhou, Gerburg M. Wulf, Mark A Rubin, Steven P Balk
    Abstract:

    Androgen receptor (AR) interacts with beta-catenin and can suppress its coactivation of T cell factor 4 (Tcf4) in prostate cancer (PCa) cells. PIN1 is a peptidyl-prolyl cis/trans isomerase that stabilizes beta-catenin by inhibiting its binding to the adenomatous polyposis coli gene product and subsequent glycogen synthase kinase 3beta (GSK-3beta)-dependent degradation. Higher PIN1 expression in primary PCa is correlated with disease recurrence, and this study found that PIN1 expression was markedly increased in metastatic PCa. Consistent with this result, increased expression of PIN1 in transfected LNCaP PCa cells strongly accelerated tumor growth in vivo in immunodeficient mice. PIN1 expression in LNCaP cells enhanced beta-catenin/Tcf4 transcriptional activity, as assessed using Tcf4-regulated reporter genes, and increased expression of endogenous Tcf4 and c-myc. However, in contrast to results in cells with intact PTEN and active GSK-3beta, PIN1 expression in LNCaP PCa cells, which are PTEN deficient, did not increase beta-catenin. Instead, PIN1 expression markedly inhibited the beta-catenin interaction with AR, and PIN1 abrogated the ability of AR to antagonize beta-catenin/Tcf4 binding and transcriptional activity. These findings demonstrate that AR can suppress beta-catenin signaling, that the AR-beta-catenin interaction can be regulated by PIN1, and that abrogation of this interaction can enhance beta-catenin/Tcf4 signaling and contribute to aggressive biological behavior in PCa.

  • the prolyl isomerase PIN1 is a novel prognostic marker in human prostate cancer
    Cancer Research, 2003
    Co-Authors: Gustavo Ayala, Gerburg M. Wulf, Janusz M Sowadski, Dagong Wang, Anna Frolov, Thomas M Wheeler, Lere Bao
    Abstract:

    Prostate cancer (PCa) is the most common male cancer in the United States. A major challenge that remains is to predict the clinical outcome in managing PCa patients. The prolyl isomerase PIN1 has been shown to be overexpressed in some human cancer tissues and thought to be an important player in several oncogenic pathways. However, the relationship between PIN1 expression and clinical outcome of cancer patients has not been explored. In this study, we investigated the role of PIN1 in human PCa progression and its clinicopathological significance. Immunohistochemical assessment with affinity-purified polyclonal PIN1-specific antibodies was performed on formalin-fixed paraffin sections of tissue microarray composed of 580 radical prostatectomy specimens. As determined by visual semiquantitation and confirmed by automated image analysis quantitation, PIN1 expression was positively correlated with clinical stage. Furthermore, Cox survival analysis results indicated that patients with a higher PIN1 expression had a significantly higher probability of recurrence than their counterparts with low PIN1 expression, as defined by a serum prostate-specific antigen level of > or =0.4 ng/ml on two consecutive occasions after radical prostatectomy. In addition, patients with high PIN1 expression had almost 4 times the risk of having earlier recurrence than those with low PIN1 expression; patients with a very high level had 8.1 times the risk of an earlier recurrence than a low PIN1 expresser. PIN1 was also an excellent predictor of recurrence in the subset of patients with Gleason score 6 or 7 when analyzed separately: a patient with high PIN1 expression had 8.6 times the risk of having earlier recurrence than one with low PIN1 expression. PIN1 expression is as good as or better than currently used postoperatively available clinicopathological parameters and potentially could be used in the preoperative setting to assist in choice of treatment. Thus, this study suggests a role for PIN1 expression as a potentially excellent prognostic marker in PCa and suggests that PIN1 may also serve as a novel therapeutic target for PCa.

Takafumi Uchida - One of the best experts on this subject based on the ideXlab platform.

  • role of prolyl isomerase PIN1 in pathogenesis of diseases and remedy for the diseases from natural products
    Current Drug Targets, 2014
    Co-Authors: Katsuhiko Takahashi, Chiyoko Uchida, Taiki Shimizu, Keita Kosaka, Masafumi Hidaka, Takafumi Uchida
    Abstract:

    The peptidyl prolyl cis/trans isomerase PIN1, the human ortholog of yeast Ess1 specifically isomerizes peptide bindings of pSer/pThr-Pro residues in various proteins, and regulates the expression levels and functions of phosphorylated proteins. Activation of PIN1 is associated with pathology of a variety of diseases, such as cancer, Alzheimer's disease, infectious diseases and so on. Therefore, regulatory compounds for PIN1 can be applied as a clinical medicine against these diseases. Many chemists have exerted themselves to synthesize the inhibitors based on the 3D structure of PIN1. We have screened for the inhibitors against PIN1 from the natural products including the functional foods. Here we review the PIN1-associated pathology and the known inhibitors identified from natural products. And we introduce the screening methods targeting PIN1 activity.

  • PIN1 promotes transforming growth factor β induced migration and invasion
    Journal of Biological Chemistry, 2010
    Co-Authors: Isao Matsuura, Takafumi Uchida, Akihide Ryo, Keng Nan Chiang, Chen Yu Lai, Guannan Wang, Romila Ramkumar, Fang Liu
    Abstract:

    Transforming growth factor-β (TGF-β) regulates a wide variety of biological activities. It induces potent growth-inhibitory responses in normal cells but promotes migration and invasion of cancer cells. Smads mediate the TGF-β responses. TGF-β binding to the cell surface receptors leads to the phosphorylation of Smad2/3 in their C terminus as well as in the proline-rich linker region. The serine/threonine phosphorylation sites in the linker region are followed by the proline residue. PIN1, a peptidyl-prolyl cis/trans isomerase, recognizes phosphorylated serine/threonine-proline motifs. Here we show that Smad2/3 interacts with PIN1 in a TGF-β-dependent manner. We further show that the phosphorylated threonine 179-proline motif in the Smad3 linker region is the major binding site for PIN1. Although epidermal growth factor also induces phosphorylation of threonine 179 and other residues in the Smad3 linker region the same as TGF-β, PIN1 is unable to bind to the epidermal growth factor-stimulated Smad3. Further analysis suggests that phosphorylation of Smad3 in the C terminus is necessary for the interaction with PIN1. Depletion of PIN1 by small hairpin RNA does not significantly affect TGF-β-induced growth-inhibitory responses and a number of TGF-β/Smad target genes analyzed. In contrast, knockdown of PIN1 in human PC3 prostate cancer cells strongly inhibited TGF-β-mediated migration and invasion. Accordingly, TGF-β induction of N-cadherin, which plays an important role in migration and invasion, is markedly reduced when PIN1 is depleted in PC3 cells. Because PIN1 is overexpressed in many cancers, our findings highlight the importance of PIN1 in TGF-β-induced migration and invasion of cancer cells.

  • the peptidyl prolyl isomerase PIN1 determines parathyroid hormone mrna levels and stability in rat models of secondary hyperparathyroidism
    Journal of Clinical Investigation, 2009
    Co-Authors: Morris Nechama, Takafumi Uchida, Irit Mor Yoseflevi, Justin Silver, Tally Navehmany
    Abstract:

    Secondary hyperparathyroidism is a major complication of chronic kidney disease (CKD). In experimental models of secondary hyperparathyroidism induced by hypocalcemia or CKD, parathyroid hormone (PTH) mRNA levels increase due to increased PTH mRNA stability. K-homology splicing regulator protein (KSRP) decreases the stability of PTH mRNA upon binding a cis-acting element in the PTH mRNA 3′ UTR region. As the peptidyl-prolyl isomerase (PPIase) PIN1 has recently been shown to regulate the turnover of multiple cytokine mRNAs, we investigated the role of PIN1 in regulating PTH mRNA stability in rat parathyroids and transfected cells. The data generated were consistent with PIN1 being a PTH mRNA destabilizing protein. Initial analysis indicated that PIN1 activity was decreased in parathyroid protein extracts from both hypocalcemic and CKD rats and that pharmacologic inhibition of PIN1 increased PTH mRNA levels posttranscriptionally in rat parathyroid and in transfected cells. PIN1 mediated its effects via interaction with KSRP, which led to KSRP dephosphorylation and activation. In the rat parathyroid, PIN1 inhibition decreased KSRP–PTH mRNA interactions, increasing PTH mRNA levels. Furthermore, PIN1–/– mice displayed increased serum PTH and PTH mRNA levels, suggesting that PIN1 determines basal PTH expression in vivo. These results demonstrate that PIN1 is a key mediator of PTH mRNA stability and indicate a role for PIN1 in the pathogenesis of secondary hyperparathyroidism in individuals with CKD.

  • prolyl isomerase PIN1 new findings of post translational modifications and physiological substrates in cancer asthma and alzheimer s disease
    Cellular and Molecular Life Sciences, 2008
    Co-Authors: C Uchida, K Takahashi, R W Shin, Kiyoe Shimazaki, Takafumi Uchida
    Abstract:

    The peptidyl prolyl cis/trans isomerase PIN1 specifically binds phosphorylated Ser/Thr-Pro protein motifs and catalyzes the cis/trans isomerization of the peptide bond. Accumulating studies have revealed that PIN1 isomerase activity is regulated by its post-translational modifications, including phosphorylation and oxidation. Various transcription factors and regulators have been identified as substrates for PIN1. It enhances AP-1 activity via isomerization of both c-Jun and c-Fos for cellular proliferation and stabilizes the oncosuppressors p53 and p73 against DNA damage at the checkpoint. We demonstrated the association between the intracellular form of Notch1 (NIC) and PIN1 by analyzing PIN1/p53 double-knockout mice. PIN1 also regulates the post-transcriptional level of some cytokines, associated with asthma, that possess 3′ untranslated region AU-rich elements (AREs) via interaction withAUF1, the nucleoprotein in the ARE-binding complex. PIN1 has been identified as the molecular partner of tau and amyloid precursor protein (APP), the key factors of Alzheimer’s disease (AD). It interacts with the phosphorylated Thr-231 of tau and regulates its activity to bind microtubules. It further interacts with the phosphorylated Thr-668 of APP and affects its metabolism. Thus, PIN1 is probably involved in the pathogenesis of human diseases, including cancer, asthma, and AD, presenting an attractive target for future therapeutical drugs.

  • opposite regulation of oligodendrocyte apoptosis by jnk3 and PIN1 after spinal cord injury
    The Journal of Neuroscience, 2007
    Co-Authors: Chhavy Tep, Takafumi Uchida, Xiao Zhen Zhou, Tae Y Yune, Sung Ok Yoon
    Abstract:

    Although oligodendrocytes undergo apoptosis after spinal cord injury, molecular mechanisms responsible for their death have been unknown. We report that oligodendrocyte apoptosis is regulated oppositely by c-Jun N-terminal kinase 3 (JNK3) and protein interacting with the mitotic kinase, never in mitosis A I (PIN1), the actions of which converge on myeloid cell leukemia sequence-1 (Mcl-1). Activated after injury, JNK3 induces cytochrome c release by facilitating the degradation of Mcl-1, the stability of which is maintained in part by PIN1. PIN1 binds Mcl-1 at its constitutively phosphorylated site, Thr163Pro, and stabilizes it by inhibiting ubiquitination. After injury JNK3 phosphorylates Mcl-1 at Ser121Pro, facilitating the dissociation of PIN1 from Mcl-1. JNK3 thus induces Mcl-1 degradation by counteracting the protective binding of PIN1. These results are confirmed by the opposing phenotypes observed between JNK3-/- and PIN1-/- mice: oligodendrocyte apoptosis and cytochrome c release are reduced in JNK3-/- but elevated in PIN1-/- mice. This report thus unveils a mechanism by which cytochrome c release is under the opposite control of JNK3 and PIN1, regulators for which the activities are intricately coupled.

Yihcherng Liou - One of the best experts on this subject based on the ideXlab platform.

  • prolyl isomerase PIN1 stabilizes and activates orphan nuclear receptor tr3 to promote mitogenesis
    Oncogene, 2012
    Co-Authors: Hangzi Chen, Weijia Wang, Q Wen, B X Zhao, W Zhou, Y Xia, Qiaoyun Yang, Choy L Hew, Yihcherng Liou
    Abstract:

    PIN1 regulates a subset of phosphoproteins by isomerizing phospho-Ser/Thr-Pro motifs via a 'post-phosphorylation' mechanism. Here, we characterize TR3 as a novel PIN1 substrate, and the mitogenic function of TR3 depends on PIN1-induced isomerization. There are at least three phospho-Ser-Pro motifs on TR3 that bind to PIN1. The Ser95-Pro motif of TR3 is the key site through which PIN1 enhances TR3 stability by retarding its degradation. PIN1 can also catalyze TR3 through phospho-Ser431-Pro motif, which is phosphorylated by extracellular signal-regulated kinase 2 (ERK2), resulting in enhanced TR3 transactivation. Furthermore, PIN1 not only facilitates TR3 targeting to the promoter of cyclin D2, a novel downstream target of TR3, but also promotes TR3 to recruit p300, thereby inducing cell proliferation. Importantly, we found that PIN1 is indispensable for TR3 to promote tumor growth both in vitro and in vivo. Our study thus suggests that PIN1 has an important role in cell proliferation by isomerizing TR3.

  • PIN1 has opposite effects on wild type and p301l tau stability and tauopathy
    Journal of Clinical Investigation, 2008
    Co-Authors: Jormay Lim, Greg Finn, Martin Balastik, Kazuhiro Nakamura, Tae Ho Lee, Yihcherng Liou, Lucia Pastorino, Anyang Sun, Virginia M Y Lee
    Abstract:

    Tau pathology is a hallmark of many neurodegenerative diseases including Alzheimer disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Genetic tau mutations can cause FTDP-17, and mice overexpressing tau mutants such as P301L tau are used as AD models. However, since no tau mutations are found in AD, it remains unclear how appropriate tau mutant mice are as an AD model. The prolyl isomerase PIN1 binds and isomerizes tau and has been implicated in protecting against neurodegeneration, but whether such PIN1 regulation is affected by tau mutations is unknown. Consistent with earlier findings that PIN1 KO induces tauopathy, here we demonstrate that PIN1 knockdown or KO increased WT tau protein stability in vitro and in mice and that PIN1 overexpression suppressed the tauopathy phenotype in WT tau transgenic mice. Unexpectedly, PIN1 knockdown or KO decreased P301L tau protein stability and abolished its robust tauopathy phenotype in mice. In contrast, PIN1 overexpression exacerbated the tauopathy phenotype in P301L tau mice. Thus, PIN1 has opposite effects on the tauopathy phenotype depending on whether the tau is WT or a P301L mutant, indicating the need for disease-specific therapies for tauopathies.

  • a suppressive role of the prolyl isomerase PIN1 in cellular apoptosis mediated by the death associated protein daxx
    Journal of Biological Chemistry, 2007
    Co-Authors: Akihide Ryo, Mayuko Nishi, Yihcherng Liou, Sam W Lee, Akiko Hirai, Kilian Perrem, Shengcai Lin, Hisashi Hirano, Ichiro Aoki
    Abstract:

    The death-associated protein Daxx is a multifunctional factor that regulates a variety of cellular processes, including transcription and apoptosis. Several previous reports have indicated that Daxx is induced upon oxidative stress and is then subjected to phosphorylation-based functional modification. However, the precise molecular events underlying these phosphorylation events remain largely unknown. We report in our current study that the peptidyl-prolyl isomerase PIN1 is highly overexpressed in malignant human gliomas and inhibits Daxx-mediated cellular apoptosis. The targeted inhibition of PIN1 by small interfering RNA in A172 glioblastoma cells significantly enhances the apoptotic response induced by hydrogen peroxide or stimulatory Fas antibodies. This is in turn accompanied by the increased induction of Daxx and the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase pathway. Furthermore, PIN1 binds to the phosphorylated Ser178-Pro motif in the Daxx protein, and PIN1 overexpression results in the rapid degradation of Daxx via the ubiquitin-proteasome pathway. Moreover, a Daxx-S178A mutant, which cannot interact with PIN1, demonstrates higher proapoptotic activity and is refractory to PIN1-mediated antiapoptotic effects. We further found that the expression levels of PIN1 inversely correlate with the degree of Daxx nuclear accumulation in human glioblastoma tissues. These results together indicate that PIN1-mediated prolyl isomerization plays an important role in the negative regulation of Daxx and thereby inhibits the oxidative stress-induced cellular apoptotic response, particularly in malignant tumor cells where PIN1 is often overexpressed.

  • prolyl isomerase PIN1 a catalyst for oncogenesis and a potential therapeutic target in cancer
    Journal of Cell Science, 2003
    Co-Authors: Akihide Ryo, Yihcherng Liou, Gerburg M. Wulf
    Abstract:

    Phosphorylation of proteins on serine or threonine residues preceding proline (Ser/Thr-Pro) is a major intracellular signaling mechanism. The phosphorylated Ser/Thr-Pro motifs in a certain subset of phosphoproteins are isomerized specifically by the peptidyl-prolyl cis-trans isomerase PIN1. This post-phosphorylation isomerization can lead to conformational changes in the substrate proteins and modulate their functions. PIN1 interacts with a number of mitotic phosphoproteins, and plays a critical role in mitotic regulation. Recent work indicates that PIN1 is overexpressed in many human cancers and plays an important role in oncogenesis. PIN1 regulates the expression of cyclin D1 by cooperating with Ras signaling and inhibiting the interaction of beta-catenin with the tumor suppressor APC and also directly stabilizing cyclin D1 protein. Furthermore, PIN1 is an E2F target gene essential for the Neu/Ras-induced transformation of mammary epithelial cells. PIN1 is also a critical regulator of the tumor suppressor p53 during DNA damage response. Given its role in cell growth control and oncogenesis, PIN1 could represent a new anti-cancer target.

  • role of PIN1 in the regulation of p53 stability and p21 transactivation and cell cycle checkpoints in response to dna damage
    Journal of Biological Chemistry, 2002
    Co-Authors: Gerburg M. Wulf, Akihide Ryo, Yihcherng Liou, Sam W Lee
    Abstract:

    DNA damage leads to stabilization and accumulation of p53, which plays a pivotal role in transcriptional activation of p21 and cell cycle arrest. The increase in p53 stability depends critically on its phosphorylation on serine/threonine residues, including those preceding a proline (Ser(P)/Thr-Pro). The Ser(P)/Thr-Pro moiety exists in the two distinct cis and trans conformations and their conversion is catalyzed specifically by the prolyl isomerase PIN1. PIN1 regulates the conformation and function of certain phosphorylated proteins and plays an important role in cell cycle regulation, oncogenesis, and Alzheimer's disease. However, nothing is known about the role of PIN1 in DNA damage. Here we found that DNA damage enhanced the interaction between PIN1 and p53, which depended on the WW domain in PIN1 and Ser33/46-Pro motifs in p53. Furthermore, PIN1 regulates the stability of p53 and its transcriptional activity toward the p21 promoter. As a result, p53 and p21 barely increased after DNA damage in PIN1 knock-out embryonic fibroblasts or in neoplastic cells depleted of PIN1. Moreover, PIN1 null cells displayed significant defects in cell cycle checkpoints induced by DNA damage. These results demonstrate a new role of PIN1 in regulating p53 function during DNA damage.