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Molecular biological mechanism of action in cancer therapies: Juglone and its derivatives, the future of development. Biomed Pharmacother 2022; 148:112785. [PMID: 35272138 DOI: 10.1016/j.biopha.2022.112785] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 02/20/2022] [Accepted: 03/02/2022] [Indexed: 11/20/2022] Open
Abstract
Juglone (5 - hydroxy - 1, 4 - naphthalene diketone) is a kind of natural naphthoquinone, present in the roots, leaves, nut-hulls, bark and wood of walnut trees. Recent studies have found that Juglone has special significance in the treatment of cancer, which plays a significant role in the resistance of cancer cell proliferation, induction of cancer cell apoptosis, induction of autophagy, anti-angiogenesis and inhibition of cancer cell migration and invasion, etc. Additionally, its derivatives also play a tumor suppressive effect. In conclusion, Juglone and its derivatives have been identified as effective anticancer drugs. This paper reviews action mechanisms of Juglone and its derivatives in cancer treatment.
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Fagiani F, Vlachou M, Di Marino D, Canobbio I, Romagnoli A, Racchi M, Govoni S, Lanni C. Pin1 as Molecular Switch in Vascular Endothelium: Notes on Its Putative Role in Age-Associated Vascular Diseases. Cells 2021; 10:cells10123287. [PMID: 34943794 PMCID: PMC8699654 DOI: 10.3390/cells10123287] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/18/2021] [Accepted: 11/21/2021] [Indexed: 01/04/2023] Open
Abstract
By controlling the change of the backbones of several cellular substrates, the peptidyl-prolyl cis-trans isomerase Pin1 acts as key fine-tuner and amplifier of multiple signaling pathways, thereby inducing several biological consequences, both in physiological and pathological conditions. Data from the literature indicate a prominent role of Pin1 in the regulating of vascular homeostasis. In this review, we will critically dissect Pin1’s role as conformational switch regulating the homeostasis of vascular endothelium, by specifically modulating nitric oxide (NO) bioavailability. In this regard, Pin1 has been reported to directly control NO production by interacting with bovine endothelial nitric oxide synthase (eNOS) at Ser116-Pro117 (human equivalent is Ser114-Pro115) in a phosphorylation-dependent manner, regulating its catalytic activity, as well as by regulating other intracellular players, such as VEGF and TGF-β, thereby impinging upon NO release. Furthermore, since Pin1 has been found to act as a critical driver of vascular cell proliferation, apoptosis, and inflammation, with implication in many vascular diseases (e.g., diabetes, atherosclerosis, hypertension, and cardiac hypertrophy), evidence indicating that Pin1 may serve a pivotal role in vascular endothelium will be discussed. Understanding the role of Pin1 in vascular homeostasis is crucial in terms of finding a new possible therapeutic player and target in vascular pathologies, including those affecting the elderly (such as small and large vessel diseases and vascular dementia) or those promoting the full expression of neurodegenerative dementing diseases.
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Affiliation(s)
- Francesca Fagiani
- Pharmacology Section, Department of Drug Sciences, University of Pavia, V.le Taramelli 14, 27100 Pavia, Italy; (F.F.); (M.V.); (M.R.); (C.L.)
| | - Marieva Vlachou
- Pharmacology Section, Department of Drug Sciences, University of Pavia, V.le Taramelli 14, 27100 Pavia, Italy; (F.F.); (M.V.); (M.R.); (C.L.)
| | - Daniele Di Marino
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy; (D.D.M.); (A.R.)
- New York-Marche Structural Biology Center (NY-MaSBiC), Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy
| | - Ilaria Canobbio
- Department of Biology and Biotechnology, University of Pavia, V.le Taramelli 14, 27100 Pavia, Italy;
| | - Alice Romagnoli
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy; (D.D.M.); (A.R.)
- New York-Marche Structural Biology Center (NY-MaSBiC), Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy
| | - Marco Racchi
- Pharmacology Section, Department of Drug Sciences, University of Pavia, V.le Taramelli 14, 27100 Pavia, Italy; (F.F.); (M.V.); (M.R.); (C.L.)
| | - Stefano Govoni
- Pharmacology Section, Department of Drug Sciences, University of Pavia, V.le Taramelli 14, 27100 Pavia, Italy; (F.F.); (M.V.); (M.R.); (C.L.)
- Correspondence:
| | - Cristina Lanni
- Pharmacology Section, Department of Drug Sciences, University of Pavia, V.le Taramelli 14, 27100 Pavia, Italy; (F.F.); (M.V.); (M.R.); (C.L.)
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Choi MA, Saeidi S, Han HJ, Kim SJ, Kwon N, Kim DH, Min SH, Choi BY, Surh YJ. The peptidyl prolyl isomerase, PIN1 induces angiogenesis through direct interaction with HIF-2α. Biochem Biophys Res Commun 2020; 533:995-1003. [PMID: 33012513 DOI: 10.1016/j.bbrc.2020.08.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 08/07/2020] [Indexed: 12/27/2022]
Abstract
PIN1, the peptidyl-prolyl isomerase (PPIase), is an enzyme that changes the conformation of phosphoproteins. The conformational change induced by PIN1 alters the function and stability of the target proteins. PIN1 is overexpressed in many different types of malignancies, including breast, lung, cervical, brain and colorectal tumors. PIN1 overexpression has been associated with activation of multiple oncogenic signaling pathways during tumor development. Hypoxia-inducible factor 2α (HIF-2α), a transcription factor activated in hypoxia, plays a role in erythropoiesis, glycolysis, tissue invasion, metastasis and angiogenesis. In this study, we found the direct interaction between HIF-2α and PIN1 in colorectal cancer HCT116 cells. Notably, serine 16 and lysine 63 residues of PIN1 were critical for its interaction with HIF-2α. When PIN1 protein was silenced by transient transfection of PIN1 short interfering RNA, the expression of HIF-2α was attenuated under a hypoxic condition. Moreover, genetic and pharmacologic inhibition of PIN1 abrogated the expression of vascular endothelial growth factor and angiogenesis. The cycloheximide chase experiment revealed the stabilization of HIF-2α by PIN1. Both WW and PPIase domains of PIN1 appear to be critical for its interaction with HIF-2α.
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Affiliation(s)
- Min-A Choi
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea
| | - Soma Saeidi
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea
| | - Hyeong-Jun Han
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea
| | - Su-Jung Kim
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea
| | - Nayoung Kwon
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea
| | - Do-Hee Kim
- Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, Suwon, Gyeonggi-do, 16227, South Korea
| | - Sang-Hyun Min
- New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation, Daegu, 701-310, South Korea
| | - Bu Young Choi
- Department of Pharmaceutical Science and Engineering, School of Convergence Bioscience and Technology, Seowon University, Chungbuk, 28674, South Korea
| | - Young-Joon Surh
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Cancer Research Institute, Seoul National University, Seoul, 03080, South Korea.
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Nakatsu Y, Yamamotoya T, Ueda K, Ono H, Inoue MK, Matsunaga Y, Kushiyama A, Sakoda H, Fujishiro M, Matsubara A, Asano T. Prolyl isomerase Pin1 in metabolic reprogramming of cancer cells. Cancer Lett 2019; 470:106-114. [PMID: 31678165 DOI: 10.1016/j.canlet.2019.10.043] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 09/21/2019] [Accepted: 10/26/2019] [Indexed: 12/20/2022]
Abstract
Pin1 is one member of a group consisting of three prolyl isomerases. Pin1 interacts with the motif containing phospho-Ser/Thr-Pro of substrates and enhances cis-trans isomerization of peptide bonds, thereby controlling the functions of these substrates. Importantly, the Pin1 expression level is highly upregulated in most cancer cells and correlates with malignant properties, and thereby with poor outcomes. In addition, Pin1 was revealed to promote the functions of multiple oncogenes and to abrogate tumor suppressors. Accordingly, Pin1 is well recognized as a master regulator of malignant processes. Recent studies have shown that Pin1 also binds to a variety of metabolic regulators, such as AMP-activated protein kinase, acetyl CoA carboxylase and pyruvate kinase2, indicating Pin1 to have major impacts on lipid and glucose metabolism in cancer cells. In this review, we focus on the roles of Pin1 in metabolic reprogramming, such as "Warburg effects", of cancer cells. Our aim is to introduce these important roles of Pin1, as well as to present evidence supporting the possibility of Pin1 inhibition as a novel anti-cancer strategy.
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Affiliation(s)
- Yusuke Nakatsu
- Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima City, Hiroshima, Japan
| | - Takeshi Yamamotoya
- Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima City, Hiroshima, Japan
| | - Koji Ueda
- Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima City, Hiroshima, Japan
| | - Hiraku Ono
- Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan
| | - Masa-Ki Inoue
- Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima City, Hiroshima, Japan
| | - Yasuka Matsunaga
- Center for Translational Research in Infection & Inflammation, School of Medicine, Tulane University, New Orleans, LA, USA
| | - Akifumi Kushiyama
- Department of Pharmacotherapy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose City, Tokyo, 204-8588, Japan
| | - Hideyuki Sakoda
- The Division of Neurology, Respirology, Endocrinology, and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, Japan
| | - Midori Fujishiro
- Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Itabashi, Tokyo, 173-8610, Japan
| | - Akio Matsubara
- Department of Urology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Tomoichiro Asano
- Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima City, Hiroshima, Japan.
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Wang JZ, Zhang YH, Bai J, Liu YW, Du WT. PIN1, a perspective on genetic biomarker for nonalcoholic fatty liver disease (NAFLD). Metabol Open 2019; 3:100014. [PMID: 32812930 PMCID: PMC7424804 DOI: 10.1016/j.metop.2019.100014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 08/03/2019] [Accepted: 08/04/2019] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE A novel genetic and molecular basis of nonalcoholic fatty liver disease (NAFLD) was explored. STUDY DESIGN A 38-year-old male, who has no bad living and dietary habits, was diagnosed as NAFLD. The potential pathogenic role of Pin1 was evaluated by enzyme-linked immunosorbent (ELISA) assay and single nucleotide polymorphism (SNP) sequencing. RESULTS ELISA determined a six-time higher concentration of plasma Pin1 compared to our previous data. Nine PIN1 SNPs were sequenced and classified according to their NAFLD-pathogenic risks, suggesting that rs2233678 and rs2287839 may be the most important genotypes that result in Pin1 overexpression and NAFLD development. CONCLUSION In summary, this work explores a novel basis for early-onset NAFLD and highlights that elevated plasma Pin1 may predict NAFLD risk at early stage. Hypothetically, inhibiting Pin1 may benefit NAFLD prevention in the future.
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Affiliation(s)
- Jing-Zhang Wang
- Corresponding author. Affiliated Hospital, College of Medicine, Hebei University of Engineering, Handan, 056002, Hebei Province, China.
| | | | | | - Yan-Wei Liu
- Affiliated Hospital, College of Medicine, College of Life Sciences and Food Engineering, Hebei University of Engineering, Handan, 056038, PR China
| | - Wen-Tao Du
- Affiliated Hospital, College of Medicine, College of Life Sciences and Food Engineering, Hebei University of Engineering, Handan, 056038, PR China
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Kim G, Bhattarai PY, Choi HS. Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 as a molecular target in breast cancer: a therapeutic perspective of gynecological cancer. Arch Pharm Res 2019; 42:128-139. [PMID: 30684192 DOI: 10.1007/s12272-019-01122-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 01/16/2019] [Indexed: 12/11/2022]
Abstract
Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) induces conformational and functional changes to numerous key signaling molecules following proline-directed phosphorylation and its deregulation contributes to disease, particularly cancer. PIN1 is overexpressed in breast cancer, promoting cell proliferation and transformation in collaboration with several oncogenic signaling pathways, and is correlated with a poor clinical outcome. PIN1 level is also increased in certain gynecological cancers such as cervical, ovarian, and endometrial cancers. Although women with breast cancer are at risk of developing a second primary gynecological malignancy, particularly of the endometrium and ovary, the common oncogenic signaling pathway mediated by PIN1 has not been noted to date. This review discusses the roles of PIN1 in breast tumorigenesis and gynecological cancer progression, as well as the clinical effect of targeting this enzyme in breast and gynecological cancers.
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Affiliation(s)
- Garam Kim
- College of Pharmacy, Chosun University, 309 Philmundaero, Dong-gu, Gwangju, 61452, Republic of Korea
| | - Poshan Yugal Bhattarai
- College of Pharmacy, Chosun University, 309 Philmundaero, Dong-gu, Gwangju, 61452, Republic of Korea
| | - Hong Seok Choi
- College of Pharmacy, Chosun University, 309 Philmundaero, Dong-gu, Gwangju, 61452, Republic of Korea.
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Liu C, Mu C, Li Z, Xu L. Imazamethabenz inhibits human breast cancer cell proliferation, migration and invasion via combination with Pin1. Mol Med Rep 2017; 15:3210-3214. [PMID: 28350086 DOI: 10.3892/mmr.2017.6399] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 02/09/2017] [Indexed: 11/06/2022] Open
Abstract
Overexpression of peptidyl-prolyl cis/trans isomerase, NIMA interacting‑1 (Pin1) is a significant marker of the occurrence and development of tumors. In the present study, the imidazoline ketone herbicide imazamethabenz was investigated as a potential antitumor drug by inhibiting Pin1. Molecular docking and enzyme activity tests verified, for the first time, that the imidazoline ketone compound imazamethabenz effectively inhibited Pin1 in vitro. MTT assays, western blotting, wound healing assay and Matrigel invasion assays revealed that imazamethabenz induced apoptosis and inhibited migration and invasion of the breast cancer cell line MCF‑7, which overexpresses Pin1, by inhibiting the Pin1‑mediated signaling pathway involving vascular endothelial growth factor and matrix metalloproteinase 9. These findings indicated that imazamethabenz offers potential applications for the treatment of tumors as a Pin1 inhibitor.
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Affiliation(s)
- Chen Liu
- College of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Chaoyu Mu
- College of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Zeng Li
- College of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Liang Xu
- College of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
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8
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Cheng CW, Leong KW, Tse E. Understanding the role of PIN1 in hepatocellular carcinoma. World J Gastroenterol 2016; 22:9921-9932. [PMID: 28018099 PMCID: PMC5143759 DOI: 10.3748/wjg.v22.i45.9921] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 09/26/2016] [Accepted: 10/30/2016] [Indexed: 02/06/2023] Open
Abstract
PIN1 is a peptidyl-prolyl cis/trans isomerase that binds and catalyses isomerization of the specific motif comprising a phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) in proteins. PIN1 can therefore induce conformational and functional changes of its interacting proteins that are regulated by proline-directed serine/threonine phosphorylation. Through this phosphorylation-dependent prolyl isomerization, PIN1 fine-tunes the functions of key phosphoproteins (e.g., cyclin D1, survivin, β-catenin and x-protein of hepatitis B virus) that are involved in the regulation of cell cycle progression, apoptosis, proliferation and oncogenic transformation. PIN1 has been found to be over-expressed in many cancers, including human hepatocellular carcinoma (HCC). It has been shown previously that overexpression of PIN1 contributes to the development of HCC in-vitro and in xenograft mouse model. In this review, we first discussed the aberrant transcription factor expression, miRNAs dysregulation, PIN1 gene promoter polymorphisms and phosphorylation of PIN1 as potential mechanisms underlying PIN1 overexpression in cancers. Furthermore, we also examined the role of PIN1 in HCC tumourigenesis by reviewing the interactions between PIN1 and various cellular and viral proteins that are involved in β-catenin, NOTCH, and PI3K/Akt/mTOR pathways, apoptosis, angiogenesis and epithelial-mesenchymal transition. Finally, the potential of PIN1 inhibitors as an anti-cancer therapy was explored and discussed.
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Rustighi A, Zannini A, Campaner E, Ciani Y, Piazza S, Del Sal G. PIN1 in breast development and cancer: a clinical perspective. Cell Death Differ 2016; 24:200-211. [PMID: 27834957 DOI: 10.1038/cdd.2016.122] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 09/19/2016] [Accepted: 09/20/2016] [Indexed: 12/12/2022] Open
Abstract
Mammary gland development, various stages of mammary tumorigenesis and breast cancer progression have the peptidyl-prolyl cis/trans isomerase PIN1 at their centerpiece, in virtue of the ability of this unique enzyme to fine-tune the dynamic crosstalk between multiple molecular pathways. PIN1 exerts its action by inducing conformational and functional changes on key cellular proteins, following proline-directed phosphorylation. Through this post-phosphorylation signal transduction mechanism, PIN1 controls the extent and direction of the cellular response to a variety of inputs, in physiology and disease. This review discusses PIN1's roles in normal mammary development and cancerous progression, as well as the clinical impact of targeting this enzyme in breast cancer patients.
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Affiliation(s)
- Alessandra Rustighi
- National Laboratory CIB (LNCIB), Area Science Park, Padriciano 99, Trieste 34149, Italy
| | - Alessandro Zannini
- National Laboratory CIB (LNCIB), Area Science Park, Padriciano 99, Trieste 34149, Italy.,Department of Life Sciences, University of Trieste, via Weiss 2, Trieste 34128, Italy
| | - Elena Campaner
- National Laboratory CIB (LNCIB), Area Science Park, Padriciano 99, Trieste 34149, Italy.,Department of Life Sciences, University of Trieste, via Weiss 2, Trieste 34128, Italy
| | - Yari Ciani
- National Laboratory CIB (LNCIB), Area Science Park, Padriciano 99, Trieste 34149, Italy
| | - Silvano Piazza
- National Laboratory CIB (LNCIB), Area Science Park, Padriciano 99, Trieste 34149, Italy.,Bioinformatics Core Facility, Centre for Integrative Biology, CIBIO, University of Trento, Via Sommarive 18, 38123, Povo, Trento, Italy
| | - Giannino Del Sal
- National Laboratory CIB (LNCIB), Area Science Park, Padriciano 99, Trieste 34149, Italy.,Department of Life Sciences, University of Trieste, via Weiss 2, Trieste 34128, Italy
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Atabay KD, Yildiz MT, Avsar T, Karabay A, Kiliç T. Knockdown of Pin1 leads to reduced angiogenic potential and tumorigenicity in glioblastoma cells. Oncol Lett 2015; 10:2385-2389. [PMID: 26622856 DOI: 10.3892/ol.2015.3512] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 03/30/2015] [Indexed: 12/23/2022] Open
Abstract
Glioblastoma is the most common and most aggressive type of primary brain tumor. Current approaches in the treatment of glioblastoma are not effective enough to increase patient survival or prevent recurrence following surgery. Consequently, the search for potential drug targets is ongoing. Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1), an isomerase that is overexpressed in various tumors, has become an attractive molecule in cancer research. Pin1 has been reported to regulate proteins involved in essential cellular pathways that mediate cell proliferation, cell cycle progression, differentiation and apoptosis, by altering their stability and function. The results of the present study revealed that knockdown of Pin1 in glioblastoma cells using RNA interference or the selective Pin1 inhibitor, juglone, suppressed the tumorigenic features by reducing cell growth, migration and angiogenic potential. Furthermore, knockdown of Pin1 decreased the levels of vascular endothelial growth factor and matrix metallopeptidase 9, and also triggered apoptosis. Due to the fundamental roles of Pin1 in promoting tumorigenesis, Pin1 inhibitory molecules, including juglone, or alternative synthetic derivatives hold potential for the development of clinical countermeasures against glioblastoma.
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Affiliation(s)
- Kutay Deniz Atabay
- Prof. Dr. Peter Black Laboratory of Molecular Neurosurgery, Institute of Neurological Sciences, Marmara University, Istanbul, Turkey ; Department of Molecular Biology and Genetics, Faculty of Science and Letters, Istanbul Technical University, Istanbul, Turkey
| | - Mehmet Taha Yildiz
- Prof. Dr. Peter Black Laboratory of Molecular Neurosurgery, Institute of Neurological Sciences, Marmara University, Istanbul, Turkey ; Department of Biology, Faculty of Arts and Science, Fatih University, Istanbul, Turkey
| | - Timucin Avsar
- Prof. Dr. Peter Black Laboratory of Molecular Neurosurgery, Institute of Neurological Sciences, Marmara University, Istanbul, Turkey ; Department of Molecular Biology and Genetics, Faculty of Science and Letters, Istanbul Technical University, Istanbul, Turkey
| | - Arzu Karabay
- Department of Molecular Biology and Genetics, Faculty of Science and Letters, Istanbul Technical University, Istanbul, Turkey
| | - Türker Kiliç
- Prof. Dr. Peter Black Laboratory of Molecular Neurosurgery, Institute of Neurological Sciences, Marmara University, Istanbul, Turkey ; Department of Neurosurgery, Faculty of Medicine, Bahcesehir University, Istanbul, Turkey
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Shen ZJ, Malter JS. Regulation of AU-Rich Element RNA Binding Proteins by Phosphorylation and the Prolyl Isomerase Pin1. Biomolecules 2015; 5:412-34. [PMID: 25874604 PMCID: PMC4496679 DOI: 10.3390/biom5020412] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 03/23/2015] [Accepted: 03/31/2015] [Indexed: 01/19/2023] Open
Abstract
The accumulation of 3' untranslated region (3'-UTR), AU-rich element (ARE) containing mRNAs, are predominantly controlled at the post-transcriptional level. Regulation appears to rely on a variable and dynamic interaction between mRNA target and ARE-specific binding proteins (AUBPs). The AUBP-ARE mRNA recognition is directed by multiple intracellular signals that are predominantly targeted at the AUBPs. These include (but are unlikely limited to) methylation, acetylation, phosphorylation, ubiquitination and isomerization. These regulatory events ultimately affect ARE mRNA location, abundance, translation and stability. In this review, we describe recent advances in our understanding of phosphorylation and its impact on conformation of the AUBPs, interaction with ARE mRNAs and highlight the role of Pin1 mediated prolyl cis-trans isomerization in these biological process.
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Affiliation(s)
- Zhong-Jian Shen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8548, USA.
| | - James S Malter
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8548, USA.
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12
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KSHV reactivation and novel implications of protein isomerization on lytic switch control. Viruses 2015; 7:72-109. [PMID: 25588053 PMCID: PMC4306829 DOI: 10.3390/v7010072] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 12/30/2014] [Indexed: 12/26/2022] Open
Abstract
In Kaposi’s sarcoma-associated herpesvirus (KSHV) oncogenesis, both latency and reactivation are hypothesized to potentiate tumor growth. The KSHV Rta protein is the lytic switch for reactivation. Rta transactivates essential genes via interactions with cofactors such as the cellular RBP-Jk and Oct-1 proteins, and the viral Mta protein. Given that robust viral reactivation would facilitate antiviral responses and culminate in host cell lysis, regulation of Rta’s expression and function is a major determinant of the latent-lytic balance and the fate of infected cells. Our lab recently showed that Rta transactivation requires the cellular peptidyl-prolyl cis/trans isomerase Pin1. Our data suggest that proline‑directed phosphorylation regulates Rta by licensing binding to Pin1. Despite Pin1’s ability to stimulate Rta transactivation, unchecked Pin1 activity inhibited virus production. Dysregulation of Pin1 is implicated in human cancers, and KSHV is the latest virus known to co-opt Pin1 function. We propose that Pin1 is a molecular timer that can regulate the balance between viral lytic gene expression and host cell lysis. Intriguing scenarios for Pin1’s underlying activities, and the potential broader significance for isomerization of Rta and reactivation, are highlighted.
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13
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Wang JZ, Liu BG, Zhang Y. Pin1-based diagnostic and therapeutic strategies for breast cancer. Pharmacol Res 2014; 93:28-35. [PMID: 25553719 DOI: 10.1016/j.phrs.2014.12.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Revised: 12/19/2014] [Accepted: 12/19/2014] [Indexed: 01/12/2023]
Abstract
Pin1 is the only known cis-to-trans isomerase that recognizes the phosphorylated pThr/pSer-Pro motifs in many signaling molecules, playing unique roles in the pathogenesis of breast cancer. First, Pin1 is prevalently over-expressed in kinds of breast cancer cell lines and tissues, such as MDA-MB-231 cell, MCF-7 cell, Her2+, ERα+, and basal-like breast cancer subtypes. Second, Pin1 amplifies many oncogenic signaling pathways, inhibits multiple tumor suppressors, promotes the angiogenesis and metastasis of breast cancer cells, and enhances the resistance of breast cancer cells to anti-tumor medicines. Third, inhibiting Pin1 blocks most of these detrimental effects in a great number of breast cancer cell lines. These findings suggest Pin1 as a promising diagnostic biomarker as well as an efficient therapeutic target for breast cancer. It is strongly expected that a Pin1-positive subtype of breast cancers should be extremely concerned and that the therapeutic efficacy of Pin1 inhibitors on breast cancer patients should be evaluated as soon as possible. Nonetheless, Pin1-based therapeutic strategies for breast cancer still deserve some debates. Hence, we give the predictions of several important issues, such as application precondition, side effects, and personalized medication, when Pin1 inhibitors are used in the breast cancer therapy. These proposals are meaningful for the further development of Pin1-based diagnostic and therapeutic strategies in order to conquer breast cancer.
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Affiliation(s)
- Jing-Zhang Wang
- Department of Medical Technology, Affiliated Hospital, College of Medicine, Hebei University of Engineering, Handan 056002, PR China.
| | - Bao-Guo Liu
- Department of Medical Technology, Affiliated Hospital, College of Medicine, Hebei University of Engineering, Handan 056002, PR China
| | - Yong Zhang
- Department of Medical Technology, Affiliated Hospital, College of Medicine, Hebei University of Engineering, Handan 056002, PR China
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14
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Jalouli M, Déry MAC, Lafleur VN, Lamalice L, Zhou XZ, Lu KP, Richard DE. The prolyl isomerase Pin1 regulates hypoxia-inducible transcription factor (HIF) activity. Cell Signal 2014; 26:1649-56. [PMID: 24726894 DOI: 10.1016/j.cellsig.2014.04.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Revised: 04/04/2014] [Accepted: 04/04/2014] [Indexed: 12/17/2022]
Abstract
Hypoxia-inducible transcription factor-1 (HIF-1) plays a decisive role in cell survival and adaptation to hypoxic stress by controlling the expression of genes involved in oxygen homeostasis. HIF-1 activity is fine-tuned through specific post-translational modifications of its essential HIF-1α subunit. Among these modifications, phosphorylation is important for HIF-1 transcriptional activity. Studies have shown that the mitogen-activated protein kinases, p42/p44 MAPKs, directly phosphorylate HIF-1α and increase HIF-1-mediated transcription. Pin1, a peptidyl-prolyl cis/trans isomerase, targets a number of proteins containing a phosphorylated Ser/Thr-Pro motif. Pin1 isomerization causes a change in target protein conformation which can modify their activity. Here, we identify Pin1 as an important HIF-1α partner. Immunoprecipitation and pull-down studies show that Pin1 interacts with HIF-1α. We demonstrate that the interaction between Pin1 and HIF-1α is regulated through p42/p44 MAPK pathway activation. By performing proteolysis studies, our results indicate that Pin1 catalytic activity generates a conformational change in HIF-1α. Finally, our work shows that Pin1 is required for gene-specific HIF-1 transcriptional activity. Our results indicate that the prolyl isomerase Pin1 regulates HIF-1 transcriptional activity by interacting with HIF-1α and promoting conformational changes in a p42/p44 MAPK phosphorylation-dependent manner.
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Affiliation(s)
- Maroua Jalouli
- Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC G1R 3S3, Canada
| | - Marc-André C Déry
- Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC G1R 3S3, Canada
| | - Véronique N Lafleur
- Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC G1R 3S3, Canada
| | - Laurent Lamalice
- Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC G1R 3S3, Canada
| | - Xiao Zhen Zhou
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Kun Ping Lu
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Darren E Richard
- Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC G1R 3S3, Canada.
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15
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Lonati E, Brambilla A, Milani C, Masserini M, Palestini P, Bulbarelli A. Pin1, a new player in the fate of HIF-1α degradation: an hypothetical mechanism inside vascular damage as Alzheimer's disease risk factor. Front Cell Neurosci 2014; 8:1. [PMID: 24478626 PMCID: PMC3894457 DOI: 10.3389/fncel.2014.00001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Accepted: 01/01/2014] [Indexed: 11/16/2022] Open
Abstract
Aetiology of neurodegenerative mechanisms underlying Alzheimer’s disease (AD) are still under elucidation. The contribution of cerebrovascular deficiencies (such as cerebral ischemia/stroke) has been strongly endorsed in recent years. Reduction of blood supply leading to hypoxic condition is known to activate cellular responses mainly controlled by hypoxia-inducible transcription factor-1 (HIF-1). Thus alterations of oxygen responsive HIF-1α subunit in the central nervous system may contribute to the cognitive decline, especially influencing mechanisms associated to amyloid precursor protein (APP) amyloidogenic metabolism. Although HIF-1α protein level is known to be regulated by von Hippel-Lindau (VHL) ubiquitin-proteasome system, it has been recently suggested that glycogen synthase kinase-3β (Gsk-3β) promotes a VHL-independent HIF-1α degradation. Here we provide evidences that in rat primary hippocampal cell cultures, HIF-1α degradation might be mediated by a synergic action of Gsk-3β and peptidyl-prolyl cis/trans isomerase (Pin1). In post-ischemic conditions, such as those mimicked with oxygen glucose deprivation (OGD), HIF-1α protein level increases remaining unexpectedly high for long time after normal condition restoration jointly with the increase of lactate dehydrogenase (LDH) and β-secretase 1 (BACE1) protein expression (70 and 140% respectively). Interestingly the Pin1 activity decreases about 40–60% and Pin1S16 inhibitory phosphorylation significantly increases, indicating that Pin1 binding to its substrate and enzymatic activity are reduced by treatment. Co-immunoprecipitation experiments demonstrate that HIF-1α/Pin1 in normoxia are associated, and that in presence of specific Pin1 and Gsk-3β inhibitors their interaction is reduced in parallel to an increase of HIF-1α protein level. Thus we suggest that in post-OGD neurons the high level of HIF-1α might be due to Pin1 binding ability and activity reduction which affects HIF-1α degradation: an event that may highlight the relevance of ischemia/HIF-1α as a risk factor in AD pathogenesis.
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Affiliation(s)
- Elena Lonati
- Department of Health Science, University of Milano-Bicocca Monza (MI), Italy
| | - Anna Brambilla
- Department of Health Science, University of Milano-Bicocca Monza (MI), Italy
| | - Chiara Milani
- Department of Health Science, University of Milano-Bicocca Monza (MI), Italy
| | - Massimo Masserini
- Department of Health Science, University of Milano-Bicocca Monza (MI), Italy
| | - Paola Palestini
- Department of Health Science, University of Milano-Bicocca Monza (MI), Italy
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16
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Rustighi A, Zannini A, Tiberi L, Sommaggio R, Piazza S, Sorrentino G, Nuzzo S, Tuscano A, Eterno V, Benvenuti F, Santarpia L, Aifantis I, Rosato A, Bicciato S, Zambelli A, Del Sal G. Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast. EMBO Mol Med 2013; 6:99-119. [PMID: 24357640 PMCID: PMC3936488 DOI: 10.1002/emmm.201302909] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Mammary epithelial stem cells are fundamental to maintain tissue integrity. Cancer stem cells (CSCs) are implicated in both treatment resistance and disease relapse, and the molecular bases of their malignant properties are still poorly understood. Here we show that both normal stem cells and CSCs of the breast are controlled by the prolyl-isomerase Pin1. Mechanistically, following interaction with Pin1, Notch1 and Notch4, key regulators of cell fate, escape from proteasomal degradation by their major ubiquitin-ligase Fbxw7α. Functionally, we show that Fbxw7α acts as an essential negative regulator of breast CSCs' expansion by restraining Notch activity, but the establishment of a Notch/Pin1 active circuitry opposes this effect, thus promoting breast CSCs self-renewal, tumor growth and metastasis in vivo. In human breast cancers, despite Fbxw7α expression, high levels of Pin1 sustain Notch signaling, which correlates with poor prognosis. Suppression of Pin1 holds promise in reverting aggressive phenotypes, through CSC exhaustion as well as recovered drug sensitivity carrying relevant implications for therapy of breast cancers.
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MESH Headings
- Animals
- Antineoplastic Agents/therapeutic use
- Breast Neoplasms/drug therapy
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism
- Cell Line, Tumor
- F-Box Proteins/genetics
- F-Box Proteins/metabolism
- F-Box-WD Repeat-Containing Protein 7
- Female
- Humans
- Mammary Glands, Human/cytology
- Mice
- Mice, Knockout
- Mice, SCID
- NIMA-Interacting Peptidylprolyl Isomerase
- Neoplastic Stem Cells/cytology
- Neoplastic Stem Cells/metabolism
- Peptidylprolyl Isomerase/antagonists & inhibitors
- Peptidylprolyl Isomerase/genetics
- Peptidylprolyl Isomerase/metabolism
- Proto-Oncogene Proteins/genetics
- Proto-Oncogene Proteins/metabolism
- Receptor, Notch1/genetics
- Receptor, Notch1/metabolism
- Receptor, Notch4
- Receptors, Notch/genetics
- Receptors, Notch/metabolism
- Signal Transduction
- Stem Cells/cytology
- Stem Cells/metabolism
- Transplantation, Heterologous
- Triple Negative Breast Neoplasms/metabolism
- Triple Negative Breast Neoplasms/pathology
- Ubiquitin-Protein Ligases/genetics
- Ubiquitin-Protein Ligases/metabolism
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Affiliation(s)
- Alessandra Rustighi
- Laboratorio Nazionale CIB (LNCIB), Area Science ParkTrieste, Italy
- Dipartimento di Scienze della Vita, Università degli Studi di TriesteTrieste, Italy
| | - Alessandro Zannini
- Laboratorio Nazionale CIB (LNCIB), Area Science ParkTrieste, Italy
- Dipartimento di Scienze della Vita, Università degli Studi di TriesteTrieste, Italy
| | - Luca Tiberi
- Laboratorio Nazionale CIB (LNCIB), Area Science ParkTrieste, Italy
- Dipartimento di Scienze della Vita, Università degli Studi di TriesteTrieste, Italy
| | - Roberta Sommaggio
- Dipartimento di Scienze Oncologiche e Chirurgiche, Università degli Studi di Padova e Istituto Oncologico Veneto IRCCSPadova, Italy
| | - Silvano Piazza
- Laboratorio Nazionale CIB (LNCIB), Area Science ParkTrieste, Italy
| | - Giovanni Sorrentino
- Laboratorio Nazionale CIB (LNCIB), Area Science ParkTrieste, Italy
- Dipartimento di Scienze della Vita, Università degli Studi di TriesteTrieste, Italy
| | - Simona Nuzzo
- Center for Genome Research, Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio EmiliaModena, Italy
| | | | - Vincenzo Eterno
- Oncology Department IRCCS Fondazione Salvatore MaugeriPavia, Italy
| | - Federica Benvenuti
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science ParkTrieste, Italy
| | - Libero Santarpia
- Translational Research Unit, Istituto Toscano TumoriPrato, Italy
| | - Iannis Aifantis
- Howard Hughes Medical Institute and Department of Pathology, NYU School of MedicineNew York, NY, USA
| | - Antonio Rosato
- Dipartimento di Scienze Oncologiche e Chirurgiche, Università degli Studi di Padova e Istituto Oncologico Veneto IRCCSPadova, Italy
| | - Silvio Bicciato
- Center for Genome Research, Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio EmiliaModena, Italy
| | - Alberto Zambelli
- Oncology Department IRCCS Fondazione Salvatore MaugeriPavia, Italy
| | - Giannino Del Sal
- Laboratorio Nazionale CIB (LNCIB), Area Science ParkTrieste, Italy
- Dipartimento di Scienze della Vita, Università degli Studi di TriesteTrieste, Italy
- Corresponding author: Tel: +39 040 3756801; Fax +39 040 398990; E-mail:
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17
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Wang JZ, Li SR, Li YL, Zhang YZ, Zhang T, Zhao CX, Yao CX, Du LF. Could Pin1 help us conquer essential hypertension at an earlier stage? A promising early-diagnostic biomarker and its therapeutic implications for the disease. Med Hypotheses 2013; 81:931-5. [DOI: 10.1016/j.mehy.2013.08.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Revised: 08/07/2013] [Accepted: 08/22/2013] [Indexed: 10/26/2022]
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18
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Meidan R, Klipper E, Zalman Y, Yalu R. The role of hypoxia-induced genes in ovarian angiogenesis. Reprod Fertil Dev 2013; 25:343-50. [PMID: 22950963 DOI: 10.1071/rd12139] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Accepted: 07/26/2012] [Indexed: 01/23/2023] Open
Abstract
The hypoxic microenvironment that occurs in fast-growing tissue such as the corpus luteum (CL) is a major contributor to its ability to survive via the induction of an intricate vascular network. Cellular responses to hypoxia are mediated by hypoxia-inducible factor-1 (HIF-1), an oxygen-regulated transcriptional activator. HIF-1, a heterodimer consisting of a constitutively-expressed β subunit and an oxygen-regulated α subunit, binds to the hypoxia responsive element (HRE) present in the promoter regions of responsive genes. This review summarises evidence for the involvement of hypoxia and HIF-1α in CL development and function. Special emphasis is given to hypoxia-induced, luteal cell-specific expression of multiple genes (vascular endothelial growth factor A (VEGFA), fibroblast growth factor 2 (FGF-2), prokineticin receptor 2 (PK-R2), stanniocalcin 1 (STC-1) and endothelin 2 (EDN-2) that participate in the angiogenic process during CL formation.
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Affiliation(s)
- Rina Meidan
- Department of Animal Sciences, The Hebrew University of Jerusalem, The Robert H. Smith Faculty of Agriculture, Food and Environment, Rehovot 76100, Israel.
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19
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Skarzynski DJ, Piotrowska-Tomala KK, Lukasik K, Galvão A, Farberov S, Zalman Y, Meidan R. Growth and Regression in Bovine Corpora Lutea: Regulation by Local Survival and Death Pathways. Reprod Domest Anim 2013; 48 Suppl 1:25-37. [DOI: 10.1111/rda.12203] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2013] [Accepted: 05/20/2013] [Indexed: 11/30/2022]
Affiliation(s)
- DJ Skarzynski
- Department of Reproductive Immunology and Pathology; Institute of Animal Reproduction and Food Research; Polish Academy of Sciences; Olsztyn; Poland
| | - KK Piotrowska-Tomala
- Department of Reproductive Immunology and Pathology; Institute of Animal Reproduction and Food Research; Polish Academy of Sciences; Olsztyn; Poland
| | - K Lukasik
- Department of Reproductive Immunology and Pathology; Institute of Animal Reproduction and Food Research; Polish Academy of Sciences; Olsztyn; Poland
| | - A Galvão
- Department of Reproductive Immunology and Pathology; Institute of Animal Reproduction and Food Research; Polish Academy of Sciences; Olsztyn; Poland
| | - S Farberov
- Department of Animal Sciences; The Robert H. Smith Faculty of Agriculture, Food and Environment; The Hebrew University of Jerusalem; Rehovot; Israel
| | - Y Zalman
- Department of Animal Sciences; The Robert H. Smith Faculty of Agriculture, Food and Environment; The Hebrew University of Jerusalem; Rehovot; Israel
| | - R Meidan
- Department of Animal Sciences; The Robert H. Smith Faculty of Agriculture, Food and Environment; The Hebrew University of Jerusalem; Rehovot; Israel
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20
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Lv L, Zhang J, Zhang L, Xue G, Wang P, Meng Q, Liang W. Essential role of Pin1 via STAT3 signalling and mitochondria-dependent pathways in restenosis in type 2 diabetes. J Cell Mol Med 2013; 17:989-1005. [PMID: 23750710 PMCID: PMC3780535 DOI: 10.1111/jcmm.12082] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Accepted: 04/17/2013] [Indexed: 12/19/2022] Open
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.
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Affiliation(s)
- Lei Lv
- Department of Vascular Surgery, Renji Hospital, Shanghai Jiaotong University, College of Medicine, Shanghai, China
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21
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Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis. Mol Cell Biol 2013; 33:2930-49. [PMID: 23716601 DOI: 10.1128/mcb.01455-12] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The Myc oncoprotein is considered a master regulator of gene transcription by virtue of its ability to modulate the expression of a large percentage of all genes. However, mechanisms that direct Myc's recruitment to DNA and target gene selection to elicit specific cellular functions have not been well elucidated. Here, we report that the Pin1 prolyl isomerase enhances recruitment of serine 62-phosphorylated Myc and its coactivators to select promoters during gene activation, followed by promoting Myc's release associated with its degradation. This facilitates Myc's activation of genes involved in cell growth and metabolism, resulting in enhanced proproliferative activity, even while controlling Myc levels. In cancer cells with impaired Myc degradation, Pin1 still enhances Myc DNA binding, although it no longer facilitates Myc degradation. Thus, we find that Pin1 and Myc are cooverexpressed in cancer, and this drives a gene expression pattern that we show is enriched in poor-outcome breast cancer subtypes. This study provides new insight into mechanisms regulating Myc DNA binding and oncogenic activity, it reveals a novel role for Pin1 in the regulation of transcription factors, and it elucidates a mechanism that can contribute to oncogenic cooperation between Pin1 and Myc.
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22
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Prolyl Isomerase Pin1 Regulated Signaling Pathway Revealed by Pin1 +/+ and Pin1 −/− Mouse Embryonic Fibroblast Cells. Pathol Oncol Res 2013; 19:667-75. [DOI: 10.1007/s12253-013-9629-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Accepted: 03/22/2013] [Indexed: 12/20/2022]
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23
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Toko H, Konstandin MH, Doroudgar S, Ormachea L, Joyo E, Joyo AY, Din S, Gude NA, Collins B, Völkers M, Thuerauf DJ, Glembotski CC, Chen CH, Lu KP, Müller OJ, Uchida T, Sussman MA. Regulation of cardiac hypertrophic signaling by prolyl isomerase Pin1. Circ Res 2013; 112:1244-52. [PMID: 23487407 DOI: 10.1161/circresaha.113.301084] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
RATIONALE Cardiac hypertrophy results from the complex interplay of differentially regulated cascades based on the phosphorylation status of involved signaling molecules. Although numerous critical regulatory kinases and phosphatases have been identified in the myocardium, the intracellular mechanism for temporal regulation of signaling duration and intensity remains obscure. In the nonmyocyte context, control of folding, activity, and stability of proteins is mediated by the prolyl isomerase Pin1, but the role of Pin1 in the heart is unknown. OBJECTIVE To establish the role of Pin1 in the heart. METHODS AND RESULTS Here, we show that either genetic deletion or cardiac overexpression of Pin1 blunts hypertrophic responses induced by transaortic constriction and consequent cardiac failure in vivo. Mechanistically, we find that Pin1 directly binds to Akt, mitogen activated protein kinase (MEK), and Raf-1 in cultured cardiomyocytes after hypertrophic stimulation. Furthermore, loss of Pin1 leads to diminished hypertrophic signaling of Akt and MEK, whereas overexpression of Pin1 increases Raf-1 phosphorylation on the autoinhibitory site Ser259, leading to reduced MEK activation. CONCLUSIONS Collectively, these data support a role for Pin1 as a central modulator of the intensity and duration of 2 major hypertrophic signaling pathways, thereby providing a novel target for regulation and control of cardiac hypertrophy.
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Affiliation(s)
- Haruhiro Toko
- Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, CA, USA
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24
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Kim JA, Kim MR, Kim O, Phuong NTT, Yun J, Yoon J, Oh WK, Bae K, Kang KW. Amurensin G inhibits angiogenesis and tumor growth of tamoxifen-resistant breast cancer via Pin1 inhibition. Food Chem Toxicol 2012; 50:3625-34. [PMID: 22842120 DOI: 10.1016/j.fct.2012.07.027] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Revised: 07/16/2012] [Accepted: 07/18/2012] [Indexed: 02/07/2023]
Abstract
Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem among estrogen-receptor-positive breast cancer patients. We have previously reported that TAM-resistant MCF-7 (TAMR-MCF-7) cells have elevated angiogenic potential via Pin1-dependent vascular endothelial growth factor (VEGF) production. Vitis amurensis grape consumed as wine and fruit contains several resveratrol-like stilbenes or oligostilbenes. In this study, we screened for the most active compound to inhibit VEGF production from V. amurensis. Among the tested compounds, amurensin G most potently suppressed VEGF production in TAMR-MCF-7 cells. The enhanced VEGF gene transcription in TAMR-MCF-7 cells was suppressed by amurensin G. Molecular analyses using reporter genes with hypoxia response elements and activator protein-1 (AP-1) elements, and western blots revealed that the activities and the nuclear levels of hypoxia inducible factor-1 (HIF-1)α and AP-1 in TAMR-MCF-7 cells were decreased by amurensin G. Moreover, amurensin G concentration-dependently inhibited protein expression and gene transcription of Pin1 in TAMR-MCF-7 cells, which was dependent on E2F1 inhibition. Chick chorioallantoic membrane assays confirmed that amurensin G had significant antiangiogenic and antitumor growth effects in TMAR-MCF-7 cells. These results demonstrate for the first time that amurensin G may have therapeutic potential for TAM-resistant breast cancer through blocking of Pin1-mediated VEGF gene transcription.
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Affiliation(s)
- Jung-Ae Kim
- College of Pharmacy, Yeungnam University, Daegu 712-749, Republic of Korea
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25
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26
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Jin H, Jiang J, Sun L, Zheng F, Wu C, Peng L, Zhao Y, Wu X. The prolyl isomerase Pin1 is overexpressed in human esophageal cancer. Oncol Lett 2011; 2:1191-1196. [PMID: 22848287 DOI: 10.3892/ol.2011.392] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Accepted: 08/17/2011] [Indexed: 01/07/2023] Open
Abstract
Peptidyl-prolyl isomerase Pin1 specifically catalyzes the cis/trans-isomerization of proline in the target sequence of phosphorylated Ser/Thr-Pro in over 50 critical regulatory proteins. Pin1 is abnormally overexpressed in a range of human cancers, including lung, breast, colon and prostate cancers. However, few reports of Pin1 overexpression are currently available in clinical samples. Therefore, we examined the expression of Pin1 and p53 in non-pathological human tissues and esophageal cancer tissues. In esophageal cancer tissues, Pin1 and p53 immunoreactivity was detected in cancer cells in 67 and 58% of cases, respectively. Moreover, Pin1 and p53 immunoreactivity was significantly correlated with lymph node-positive disease and more advanced cancer stage. The results demonstrated that high expression levels of Pin1 correlated with high levels of p53. Therefore, Pin1 is suggested to play key roles in the regulation of esophageal cancer.
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Affiliation(s)
- Huawei Jin
- Department of Chemical Biology and The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005
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27
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Lee KY, Lee JW, Nam HJ, Shim JH, Song Y, Kang KW. PI3-kinase/p38 kinase-dependent E2F1 activation is critical for Pin1 induction in tamoxifen-resistant breast cancer cells. Mol Cells 2011; 32:107-11. [PMID: 21573702 PMCID: PMC3887657 DOI: 10.1007/s10059-011-0074-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Accepted: 04/19/2011] [Indexed: 10/18/2022] Open
Abstract
Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. We have shown that Pin1, a peptidyl prolyl isomerase, is consistently overexpressed in TAM-resistant MCF-7 cells (TAMR-MCF-7 cells) and plays a key role in the enhanced angiogenic potential of TAMR-MCF-7 cells. In the present study, we focused on signaling pathways for Pin1 up-regulation in TAMR-MCF-7 cells. Relative to MCF-7 cells, Pin1 gene transcription and E2 transcription factor1 (E2F1) expression were enhanced in TAMR-MCF-7 cells. E2F1 siRNA significantly reduced both the protein expression and the promoter transcriptional activity of Pin1. Activities of phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK) and p38 kinase were all higher in TAMR-MCF-7 cells than in control MCF-7 cells and the enhanced Pin1 and E2F1 expression in TAMR-MCF-7 cells was reversed by inhibition of PI3K or p38 kinase. Moreover, the higher production of vascular endothelial growth factor (VEGF) in TAMR-MCF-7 cells was significantly diminished by suppression of PI3K or p38 kinase. These results suggest that Pin1 overexpression and subsequent VEGF production in TAMR-MCF-7 cells are mediated through PI3-kinase or p38 kinase-dependent E2F1 activation.
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Affiliation(s)
- Kwang Youl Lee
- College of Pharmacy, Chonnam National University, Gwangju 500-757, Korea
| | | | | | - Jeong-Hyun Shim
- School of Medicine, Soonchunhyang University, Asan 336-745, Korea
| | - Youngsup Song
- The Salk Institute for Biological Studies, La Jolla, CA92037, USA
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28
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Inhibition of angiogenesis by quercetin in tamoxifen-resistant breast cancer cells. Food Chem Toxicol 2010; 48:3227-34. [DOI: 10.1016/j.fct.2010.08.028] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2010] [Revised: 08/04/2010] [Accepted: 08/20/2010] [Indexed: 12/24/2022]
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29
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Lv L, Zhou Z, Huang X, Zhao Y, Zhang L, Shi Y, Sun M, Zhang J. Inhibition of peptidyl-prolyl cis/trans isomerase Pin1 induces cell cycle arrest and apoptosis in vascular smooth muscle cells. Apoptosis 2010; 15:41-54. [PMID: 19904610 DOI: 10.1007/s10495-009-0409-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
This study was undertaken to determine the in vitro effect of lentivirus-mediated siPin1 on cell cycle and apoptosis of vascular smooth muscle cells (VSMCs). Further we sought to provide insight into the mechanisms behind these processes. Human umbilical artery smooth muscle cells (HUASMCs) were transfected with lentiviral siPin1. Real-time RT-PCR and Western blotting were used to examine Pin1 mRNA and protein expression. MTT and [(3)H]thymidine incorporation assays were employed to observe cell proliferation status. The apoptotic rate and cell cycle were analyzed by Hoechst33258 staining and flow cytometry. Finally we measured the expression of cyclin D1, beta-catenin, CDK4, cytochrome c, procaspase-3, cleaved caspase-3, procaspase-9, cleaved caspase-9, Bcl-2, Bax, STAT3, phosphorylated STAT3 and VEGF in lentiviral siPin1 infected VSMCs. Lentivirus-mediated siPin1 effectively diminished endogenous Pin1 expression in VSMCs resulting in cell cycle arrest and enhancement of apoptosis. This was accompanied by downregulation of cyclin D1, beta-catenin, CDK4, increase of Bax/Bcl-2 ratio, release of cytochrome c, and activation of caspase-3 and -9. We concluded that this effect was mediated, at least in part, via the beta-catenin/cyclin D1/CDK4 cascade, and that the mitochondrial pathway was responsible for VSMC apoptosis in the absence of Pin1. Our observations raised the possibility that Pin1 might be a potential therapeutic target to prevent stenosis.
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Affiliation(s)
- Lei Lv
- Department of Vascular Surgery, Renji Hospital, Shanghai Jiaotong University, College of Medicine, 145 Hao Shandong Zhong Road, Shanghai, China
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30
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Behrens MI, Lendon C, Roe CM. A common biological mechanism in cancer and Alzheimer's disease? Curr Alzheimer Res 2009; 6:196-204. [PMID: 19519301 DOI: 10.2174/156720509788486608] [Citation(s) in RCA: 136] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cancer and Alzheimer's disease (AD) are two common disorders for which the final pathophysiological mechanism is not yet clearly defined. In a prospective longitudinal study we have previously shown an inverse association between AD and cancer, such that the rate of developing cancer in general with time was significantly slower in participants with AD, while participants with a history of cancer had a slower rate of developing AD. In cancer, cell regulation mechanisms are disrupted with augmentation of cell survival and/or proliferation, whereas conversely, AD is associated with increased neuronal death, either caused by, or concomitant with, beta amyloid (Abeta) and tau deposition. The possibility that perturbations of mechanisms involved in cell survival/death regulation could be involved in both disorders is discussed. Genetic polymorphisms, DNA methylation or other mechanisms that induce changes in activity of molecules with key roles in determining the decision to "repair and live"- or "die" could be involved in the pathogenesis of the two disorders. As examples, the role of p53, Pin1 and the Wnt signaling pathway are discussed as potential candidates that, speculatively, may explain inverse associations between AD and cancer.
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Affiliation(s)
- M I Behrens
- Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile and Clínica Alemana Santiago, Chile.
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31
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Kim MR, Choi HS, Yang JW, Park BC, Kim JA, Kang KW. Enhancement of vascular endothelial growth factor–mediated angiogenesis in tamoxifen-resistant breast cancer cells: role of Pin1 overexpression. Mol Cancer Ther 2009; 8:2163-71. [DOI: 10.1158/1535-7163.mct-08-1061] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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32
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Tyagi N, Krishnadev O, Srinivasan N. Prediction of protein–protein interactions between Helicobacter pylori and a human host. MOLECULAR BIOSYSTEMS 2009; 5:1630-5. [DOI: 10.1039/b906543c] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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