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1
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Aziz N, Hong YH, Kim HG, Kim JH, Cho JY. Tumor-suppressive functions of protein lysine methyltransferases. Exp Mol Med 2023; 55:2475-2497. [PMID: 38036730 PMCID: PMC10766653 DOI: 10.1038/s12276-023-01117-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 08/30/2023] [Accepted: 09/05/2023] [Indexed: 12/02/2023] Open
Abstract
Protein lysine methyltransferases (PKMTs) play crucial roles in histone and nonhistone modifications, and their dysregulation has been linked to the development and progression of cancer. While the majority of studies have focused on the oncogenic functions of PKMTs, extensive evidence has indicated that these enzymes also play roles in tumor suppression by regulating the stability of p53 and β-catenin, promoting α-tubulin-mediated genomic stability, and regulating the transcription of oncogenes and tumor suppressors. Despite their contradictory roles in tumorigenesis, many PKMTs have been identified as potential therapeutic targets for cancer treatment. However, PKMT inhibitors may have unintended negative effects depending on the specific cancer type and target enzyme. Therefore, this review aims to comprehensively summarize the tumor-suppressive effects of PKMTs and to provide new insights into the development of anticancer drugs targeting PKMTs.
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Affiliation(s)
- Nur Aziz
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Yo Han Hong
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Han Gyung Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Ji Hye Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Jae Youl Cho
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
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2
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Rienzo M, Sorrentino A, Di Zazzo E, Di Donato M, Carafa V, Marino MM, De Rosa C, Gazzerro P, Castoria G, Altucci L, Casamassimi A, Abbondanza C. Searching for a Putative Mechanism of RIZ2 Tumor-Promoting Function in Cancer Models. Front Oncol 2021; 10:583533. [PMID: 33585202 PMCID: PMC7880127 DOI: 10.3389/fonc.2020.583533] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 12/08/2020] [Indexed: 12/16/2022] Open
Abstract
Positive Regulatory Domain (PRDM) gene family members commonly express two main molecular variants, the PR-plus isoform usually acting as tumor suppressor and the PR-minus one functioning as oncogene. Accordingly, PRDM2/RIZ encodes for RIZ1 (PR-plus) and RIZ2 (PR-minus). In human cancers, genetic or epigenetic modifications induce RIZ1 silencing with an expression level imbalance in favor of RIZ2 that could be relevant for tumorigenesis. Additionally, in estrogen target cells and tissues, estradiol increases RIZ2 expression level with concurrent increase of cell proliferation and survival. Several attempts to study RIZ2 function in HeLa or MCF-7 cells by its over-expression were unsuccessful. Thus, we over-expressed RIZ2 in HEK-293 cells, which are both RIZ1 and RIZ2 positive but unresponsive to estrogens. The forced RIZ2 expression increased cell viability and growth, prompted the G2-to-M phase transition and organoids formation. Accordingly, microarray analysis revealed that RIZ2 regulates several genes involved in mitosis. Consistently, RIZ silencing in both estrogen-responsive MCF-7 and -unresponsive MDA-MB-231 cells induced a reduction of cell proliferation and an increase of apoptosis rate. Our findings add novel insights on the putative RIZ2 tumor-promoting functions, although additional attempts are warranted to depict the underlying molecular mechanism.
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Affiliation(s)
- Monica Rienzo
- Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Anna Sorrentino
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Erika Di Zazzo
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.,Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Marzia Di Donato
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Vincenzo Carafa
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Michela Marino
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Caterina De Rosa
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | - Gabriella Castoria
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Amelia Casamassimi
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Ciro Abbondanza
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
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3
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Mzoughi S, Fong JY, Papadopoli D, Koh CM, Hulea L, Pigini P, Di Tullio F, Andreacchio G, Hoppe MM, Wollmann H, Low D, Caldez MJ, Peng Y, Torre D, Zhao JN, Uchenunu O, Varano G, Motofeanu CM, Lakshmanan M, Teo SX, Wun CM, Perini G, Tan SY, Ong CB, Al-Haddawi M, Rajarethinam R, Hue SSS, Lim ST, Ong CK, Huang D, Ng SB, Bernstein E, Hasson D, Wee KB, Kaldis P, Jeyasekharan A, Dominguez-Sola D, Topisirovic I, Guccione E. PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis. Nat Commun 2020; 11:3520. [PMID: 32665551 PMCID: PMC7360777 DOI: 10.1038/s41467-020-17064-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 06/01/2020] [Indexed: 01/22/2023] Open
Abstract
PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity and fate determination, often dysregulated in cancer. The PRDM15 gene is of particular interest, given its low expression in adult tissues and its overexpression in B-cell lymphomas. Despite its well characterized role in stem cell biology and during early development, the role of PRDM15 in cancer remains obscure. Herein, we demonstrate that while PRDM15 is largely dispensable for mouse adult somatic cell homeostasis in vivo, it plays a critical role in B-cell lymphomagenesis. Mechanistically, PRDM15 regulates a transcriptional program that sustains the activity of the PI3K/AKT/mTOR pathway and glycolysis in B-cell lymphomas. Abrogation of PRDM15 induces a metabolic crisis and selective death of lymphoma cells. Collectively, our data demonstrate that PRDM15 fuels the metabolic requirement of B-cell lymphomas and validate it as an attractive and previously unrecognized target in oncology.
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Affiliation(s)
- Slim Mzoughi
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jia Yi Fong
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
| | - David Papadopoli
- Lady Davis Institute, SMBD JGH, McGill University, Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, H3T 1E2, Canada
| | - Cheryl M Koh
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Laura Hulea
- Lady Davis Institute, SMBD JGH, McGill University, Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, H3T 1E2, Canada
- Maisonneuve-Rosemont Hospital Research Centre, 5415 Assumption Blvd, Montreal, QC, H1T 2M4, Canada
- Département de Médecine, Université de Montréal, CP 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, Canada
| | - Paolo Pigini
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Pharmacy and Biotechnology, University of Bologna, Via F. Selmi 3, 40126, Bologna, Italy
| | - Federico Di Tullio
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Giuseppe Andreacchio
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Pharmacy and Biotechnology, University of Bologna, Via F. Selmi 3, 40126, Bologna, Italy
| | - Michal Marek Hoppe
- Cancer Science Institute (CSI), National University of Singapore, Singapore, Singapore
| | - Heike Wollmann
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Diana Low
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Matias J Caldez
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Frontiers Research Center, Osaka University, 3-1 Yamada-oka, Suita, 565-0871, Japan
| | - Yanfen Peng
- Cancer Science Institute (CSI), National University of Singapore, Singapore, Singapore
| | - Denis Torre
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Julia N Zhao
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Oro Uchenunu
- Lady Davis Institute, SMBD JGH, McGill University, Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, H3T 1E2, Canada
| | - Gabriele Varano
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Immunology Institute and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Corina-Mihaela Motofeanu
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Manikandan Lakshmanan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Shun Xie Teo
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Cheng Mun Wun
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Giovanni Perini
- Department of Pharmacy and Biotechnology, University of Bologna, Via F. Selmi 3, 40126, Bologna, Italy
| | - Soo Yong Tan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Advanced Molecular Pathology Laboratory, IMCB, Singapore, Singapore
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chee Bing Ong
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Advanced Molecular Pathology Laboratory, IMCB, Singapore, Singapore
| | - Muthafar Al-Haddawi
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Advanced Molecular Pathology Laboratory, IMCB, Singapore, Singapore
| | - Ravisankar Rajarethinam
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Advanced Molecular Pathology Laboratory, IMCB, Singapore, Singapore
| | - Susan Swee-Shan Hue
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Hospital (NUH), Singapore, Singapore
| | - Soon Thye Lim
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Graduate Medical School, Singapore, Singapore
| | - Choon Kiat Ong
- Duke-NUS Graduate Medical School, Singapore, Singapore
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Dachuan Huang
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Siok-Bian Ng
- Cancer Science Institute (CSI), National University of Singapore, Singapore, Singapore
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Emily Bernstein
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Dan Hasson
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Keng Boon Wee
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Philipp Kaldis
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Anand Jeyasekharan
- Cancer Science Institute (CSI), National University of Singapore, Singapore, Singapore
| | - David Dominguez-Sola
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Immunology Institute and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ivan Topisirovic
- Lady Davis Institute, SMBD JGH, McGill University, Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, H3T 1E2, Canada.
- Lady Davis Institute, SMBD JGH, McGill University, Departments of Experimental Medicine and Biochemistry, McGill University, Montreal, QC, H3T 1E2, Canada.
| | - Ernesto Guccione
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Mount Sinai Center for Therapeutics Discovery, Department of Oncological and Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Casamassimi A, Rienzo M, Di Zazzo E, Sorrentino A, Fiore D, Proto MC, Moncharmont B, Gazzerro P, Bifulco M, Abbondanza C. Multifaceted Role of PRDM Proteins in Human Cancer. Int J Mol Sci 2020; 21:ijms21072648. [PMID: 32290321 PMCID: PMC7177584 DOI: 10.3390/ijms21072648] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/29/2020] [Accepted: 04/08/2020] [Indexed: 12/15/2022] Open
Abstract
The PR/SET domain family (PRDM) comprise a family of genes whose protein products share a conserved N-terminal PR [PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ1 (retinoblastoma protein-interacting zinc finger gene 1)] homologous domain structurally and functionally similar to the catalytic SET [Su(var)3-9, enhancer-of-zeste and trithorax] domain of histone methyltransferases (HMTs). These genes are involved in epigenetic regulation of gene expression through their intrinsic HMTase activity or via interactions with other chromatin modifying enzymes. In this way they control a broad spectrum of biological processes, including proliferation and differentiation control, cell cycle progression, and maintenance of immune cell homeostasis. In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications. A common characteristic of most PRDM genes is to encode for two main molecular variants with or without the PR domain. They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed. In this scenario, PRDM proteins are involved in cancer onset, invasion, and metastasis and their altered expression is related to poor prognosis and clinical outcome. These functions strongly suggest their potential use in cancer management as diagnostic or prognostic tools and as new targets of therapeutic intervention.
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Affiliation(s)
- Amelia Casamassimi
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 80138 Naples, Italy; (E.D.Z.); (A.S.)
- Correspondence: (A.C.); (C.A.); Tel.: +39-081-566-7579 (A.C.); +39-081-566-7568 (C.A.)
| | - Monica Rienzo
- Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy;
| | - Erika Di Zazzo
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 80138 Naples, Italy; (E.D.Z.); (A.S.)
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy;
| | - Anna Sorrentino
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 80138 Naples, Italy; (E.D.Z.); (A.S.)
| | - Donatella Fiore
- Department of Pharmacy, University of Salerno, 84084 Fisciano (SA), Italy; (D.F.); (M.C.P.); (P.G.)
| | - Maria Chiara Proto
- Department of Pharmacy, University of Salerno, 84084 Fisciano (SA), Italy; (D.F.); (M.C.P.); (P.G.)
| | - Bruno Moncharmont
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy;
| | - Patrizia Gazzerro
- Department of Pharmacy, University of Salerno, 84084 Fisciano (SA), Italy; (D.F.); (M.C.P.); (P.G.)
| | - Maurizio Bifulco
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, 80131 Naples, Italy;
| | - Ciro Abbondanza
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 80138 Naples, Italy; (E.D.Z.); (A.S.)
- Correspondence: (A.C.); (C.A.); Tel.: +39-081-566-7579 (A.C.); +39-081-566-7568 (C.A.)
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Critical Function of PRDM2 in the Neoplastic Growth of Testicular Germ Cell Tumors. BIOLOGY 2016; 5:biology5040054. [PMID: 27983647 PMCID: PMC5192434 DOI: 10.3390/biology5040054] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/14/2016] [Accepted: 12/05/2016] [Indexed: 12/30/2022]
Abstract
Testicular germ cell tumors (TGCTs) derive from primordial germ cells. Their maturation is blocked at different stages, reflecting histological tumor subtypes. A common genetic alteration in TGCT is a deletion of the chromosome 1 short arm, where the PRDM2 gene, belonging to the Positive Regulatory domain gene (PRDM) family, is located. Expression of PRDM2 gene is shifted in different human tumors, where the expression of the two principal protein forms coded by PRDM2 gene, RIZ1 and RIZ2, is frequently unbalanced. Therefore, PRDM2 is actually considered a candidate tumor suppressor gene in different types of cancer. Although recent studies have demonstrated that PRDM gene family members have a pivotal role during the early stages of testicular development, no information are actually available on the involvement of these genes in TGCTs. In this article we show by qRT-PCR analysis that PRDM2 expression level is modulated by proliferation and differentiation agents such as estradiol, whose exposure during fetal life is probably an important risk factor for TGCTs development in adulthood. Furthermore in normal and cancer germ cell lines, PRDM2 binds estradiol receptor α (ERα) and influences proliferation, survival and apoptosis, as previously reported using MCF-7 breast cancer cell line, suggesting a potential tumor-suppressor role in TGCT formation.
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Chen Y, Zhang P, Wang Y, Dong S, Liu Y. Construction of PR domain eukaryotic expression vector and its inhibitory effect on esophageal cancer cells. Chin J Cancer Res 2013; 25:493-9. [PMID: 24255571 DOI: 10.3978/j.issn.1000-9604.2013.09.02] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Accepted: 08/30/2013] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE PR domain is responsible for the tumor suppressing activity of RIZ1. The study aimed to construct human PR domain eukaryotic expression vectors, transfect human esophageal cancer cells (TE13), and evaluate the anticancer activity of PR domain on human esophageal cancer TE13 cells. METHODS First, mRNA was extracted from human esophageal cancer tissue by RT-PCR, then reverse-transcribed to cDNA. After amplifying from the DNA template, PR domain was linked to T vector. Second, after extraction, PR domain was cut using enzyme and linked to pcDNA3.1(+). Then, the plasmid was transfered to Trans1-T1 phage resistant competent cells, following by extracting the ultrapure plasmid, and transfecting into TE13 cells. In the end, the protein expression of pcDNA3.1(+)/PR domain in TE13 was detected by Western blot, and the apoptosis of TE13 by technique of flow cytometry. RESULTS More than 5,000 bp purposed band of pcDNA3.1(+)/PR domain plasmid was found by agarose gel electrophoresis. After transfection, the PR domain (molecular weight of about 28 Da) was found only in 3, 4 and 5 groups by Western blot. Flow cytometry assay showed apoptosis in experimental group was significantly more than that in the control group (P<0.05). CONCLUSIONS The PR domain eukaryotic expression vector was constructed successfully. The protein of the PR domain could be expressed in esophageal cancer TE13 cells firmly after transfection, and a single PR domain could promote apoptosis of TE13 cells.
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Affiliation(s)
- Yuan Chen
- Department of Cardiothoracic Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
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Gewies A, Castineiras-Vilarino M, Ferch U, Jährling N, Heinrich K, Hoeckendorf U, Przemeck GKH, Munding M, Groß O, Schroeder T, Horsch M, Karran EL, Majid A, Antonowicz S, Beckers J, Hrabé de Angelis M, Dodt HU, Peschel C, Förster I, Dyer MJS, Ruland J. Prdm6 is essential for cardiovascular development in vivo. PLoS One 2013; 8:e81833. [PMID: 24278461 PMCID: PMC3836774 DOI: 10.1371/journal.pone.0081833] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Accepted: 10/28/2013] [Indexed: 11/18/2022] Open
Abstract
Members of the PRDM protein family have been shown to play important roles during embryonic development. Previous in vitro and in situ analyses indicated a function of Prdm6 in cells of the vascular system. To reveal physiological functions of Prdm6, we generated conditional Prdm6-deficient mice. Complete deletion of Prdm6 results in embryonic lethality due to cardiovascular defects associated with aberrations in vascular patterning. However, smooth muscle cells could be regularly differentiated from Prdm6-deficient embryonic stem cells and vascular smooth muscle cells were present and proliferated normally in Prdm6-deficient embryos. Conditional deletion of Prdm6 in the smooth muscle cell lineage using a SM22-Cre driver line resulted in perinatal lethality due to hemorrhage in the lungs. We thus identified Prdm6 as a factor that is essential for the physiological control of cardiovascular development.
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Affiliation(s)
- Andreas Gewies
- Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Laboratory of Signaling in the Immune System, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Mercedes Castineiras-Vilarino
- Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Uta Ferch
- Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Nina Jährling
- Department of Bioelectronics, Institute of Solid State Electronics, Vienna University of Technology, Vienna, Austria
- Center for Brain Research, Section of Bioelectronics, Medical University of Vienna, Vienna, Austria
- Department of Neurobiology, University of Oldenburg, Oldenburg, Germany
| | - Katja Heinrich
- Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Ulrike Hoeckendorf
- Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
- Department of Internal Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Gerhard K. H. Przemeck
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Matthias Munding
- Helmholtz Zentrum München, German Research Center for Environmental Health, Research Unit Stem Cell Dynamics, Neuherberg, Germany
| | - Olaf Groß
- Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Timm Schroeder
- Helmholtz Zentrum München, German Research Center for Environmental Health, Research Unit Stem Cell Dynamics, Neuherberg, Germany
| | - Marion Horsch
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - E. Loraine Karran
- MRC Toxicology Unit and Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom
| | - Aneela Majid
- MRC Toxicology Unit and Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom
| | - Stefan Antonowicz
- MRC Toxicology Unit and Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom
| | - Johannes Beckers
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Chair of Experimental Genetics, Technische Universität München, Freising-Weihenstephan, Germany
| | - Martin Hrabé de Angelis
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Chair of Experimental Genetics, Technische Universität München, Freising-Weihenstephan, Germany
| | - Hans-Ulrich Dodt
- Department of Bioelectronics, Institute of Solid State Electronics, Vienna University of Technology, Vienna, Austria
- Center for Brain Research, Section of Bioelectronics, Medical University of Vienna, Vienna, Austria
| | - Christian Peschel
- Department of Internal Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Irmgard Förster
- Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany
- Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Martin J. S. Dyer
- MRC Toxicology Unit and Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom
| | - Jürgen Ruland
- Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Laboratory of Signaling in the Immune System, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Infection Research (DZIF), partner site München, Munich, Germany
- * E-mail:
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From notochord formation to hereditary chordoma: the many roles of Brachyury. BIOMED RESEARCH INTERNATIONAL 2013; 2013:826435. [PMID: 23662285 PMCID: PMC3626178 DOI: 10.1155/2013/826435] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 02/22/2013] [Indexed: 12/25/2022]
Abstract
Chordoma is a rare, but often malignant, bone cancer that preferentially affects the axial skeleton and the skull base. These tumors are both sporadic and hereditary and appear to occur more frequently after the fourth decade of life; however, modern technologies have increased the detection of pediatric chordomas. Chordomas originate from remnants of the notochord, the main embryonic axial structure that precedes the backbone, and share with notochord cells both histological features and the expression of characteristic genes. One such gene is Brachyury, which encodes for a sequence-specific transcription factor. Known for decades as a main regulator of notochord formation, Brachyury has recently gained interest as a biomarker and causative agent of chordoma, and therefore as a promising therapeutic target. Here, we review the main characteristics of chordoma, the molecular markers, and the clinical approaches currently available for the early detection and possible treatment of this cancer. In particular, we report on the current knowledge of the role of Brachyury and of its possible mechanisms of action in both notochord formation and chordoma etiogenesis.
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9
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Vrzalikova K, Leonard S, Fan Y, Bell A, Vockerodt M, Flodr P, Wright KL, Rowe M, Tao Q, Murray PG. Hypomethylation and Over-Expression of the Beta Isoform of BLIMP1 is Induced by Epstein-Barr Virus Infection of B Cells; Potential Implications for the Pathogenesis of EBV-Associated Lymphomas. Pathogens 2012; 1:83-101. [PMID: 25436766 PMCID: PMC4235687 DOI: 10.3390/pathogens1020083] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2012] [Revised: 09/19/2012] [Accepted: 09/24/2012] [Indexed: 12/03/2022] Open
Abstract
B-lymphocyte-induced maturation protein 1 (BLIMP1) exists as two major isoforms, α and β, which arise from alternate promoters. Inactivation of the full length BLIMP1α isoform is thought to contribute to B cell lymphomagenesis by blocking post-germinal centre (GC) B cell differentiation. In contrast, the shorter β isoform is functionally impaired and over-expressed in several haematological malignancies, including diffuse large B cell lymphomas (DLBCL). We have studied the influence on BLIMP1β expression of the Epstein-Barr virus (EBV), a human herpesvirus that is implicated in the pathogenesis of several GC-derived lymphomas, including a subset of DLBCL and Hodgkin’s lymphoma (HL). We show that BLIMP1β expression is increased following the EBV infection of normal human tonsillar GC B cells. We also show that this change in expression is accompanied by hypomethylation of the BLIMP1β-specific promoter. Furthermore, we confirmed previous reports that the BLIMP1β promoter is hypomethylated in DLBCL cell lines and show for the first time that BLIMP1β is hypomethylated in the Hodgkin/Reed-Sternberg (HRS) cells of HL. Our results provide evidence in support of a role for BLIMP1β in the pathogenesis of EBV-associated B cell lymphomas.
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Affiliation(s)
| | - Sarah Leonard
- School of Cancer Sciences, University of Birmingham, B15 2TT, UK.
| | - Yichao Fan
- The Cancer Epigenetics Laboratory, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, 999077, Hong Kong.
| | - Andrew Bell
- School of Cancer Sciences, University of Birmingham, B15 2TT, UK.
| | | | - Patrik Flodr
- Laboratory of Molecular Pathology, Department of Pathology, and Institute of Molecular and Translation Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, 779 00, Czech Republic.
| | - Kenneth L Wright
- H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, MRC-4 East, Tampa, FL 33612, USA.
| | - Martin Rowe
- School of Cancer Sciences, University of Birmingham, B15 2TT, UK.
| | - Qian Tao
- The Cancer Epigenetics Laboratory, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, 999077, Hong Kong.
| | - Paul G Murray
- School of Cancer Sciences, University of Birmingham, B15 2TT, UK.
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10
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Máximo V, Lima J, Prazeres H, Soares P, Sobrinho-Simões M. The biology and the genetics of Hurthle cell tumors of the thyroid. Endocr Relat Cancer 2012; 19:R131-47. [PMID: 22514109 DOI: 10.1530/erc-11-0354] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The biology and the genetics of Hürthle cell tumors are reviewed starting from the characterization and differential diagnosis of the numerous benign and malignant, neoplastic and nonneoplastic lesions of the thyroid in which Hürthle cell transformation is frequently observed. The clinicopathologic and molecular evidence obtained from the comparative study of the aforementioned conditions indicate that Hürthle cell appearance represents a phenotype that is superimposed on the genotypic and conventional histopathologic features of the tumors. Hürthle cell tumors differ from their non-Hürthle counterparts regarding the prevalence of large deletions of mitochondrial DNA (mtDNA), mutations of mtDNA genes coding for oxidative phosphorylation (OXPHOS) proteins (namely mutations of complex I subunit genes) and mutations of nuclear genes coding also for mitochondrial OXPHOS proteins. Such mitochondrial alterations lead to energy production defects in Hürthle cell tumors; the increased proliferation of mitochondria may reflect a compensatory mechanism for such defects and is associated with the overexpression of factors involved in mitochondrial biogenesis. The mitochondrial abnormalities are also thought to play a major role in the predisposition for necrosis instead of apoptosis which seems to be blocked in most Hürthle cell tumors. Finally, the results obtained in experimental models using cybrid cell lines and the data obtained from histopathologic and molecular studies of familial Hürthle cell tumors are used, together with the aforementioned genetic and epigenetic alterations, to progress in the understanding of the mechanisms through which mitochondrial abnormalities may be involved in the different steps of thyroid carcinogenesis, from tumor initiation to metastization.
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Affiliation(s)
- Valdemar Máximo
- Institute of Pathology and Immunology of the University of Porto (IPATIMUP), Rua Roberto Frias s/n, 4200-465 Porto, Portugal
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11
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Abbondanza C, De Rosa C, D'Arcangelo A, Pacifico M, Spizuoco C, Piluso G, Di Zazzo E, Gazzerro P, Medici N, Moncharmont B, Puca GA. Identification of a functional estrogen-responsive enhancer element in the promoter 2 of PRDM2 gene in breast cancer cell lines. J Cell Physiol 2012; 227:964-75. [PMID: 21503890 DOI: 10.1002/jcp.22803] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The retinoblastoma protein-interacting zinc-finger (RIZ) gene, also known as PRDM2, encodes two protein products, RIZ1 and RIZ2, differing for the presence of a 202 aa domain, called PR domain, at the N-terminus of the RIZ1 molecule. While the histone H3 K9 methyltransferase activity of RIZ1 is associated with the negative control of cell proliferation, no information is currently available on either expression regulation of the RIZ2 form or on its biological activity. RIZ proteins act as ER co-activators and promote optimal estrogen response in female reproductive tissues. In estrogen-responsive cells, 17-β estradiol modulates RIZ gene expression producing a shift in the balanced expression of the two forms. Here, we demonstrate that an estrogen-responsive element (ERE) within the RIZ promoter 2 is regulated in a ligand-specific manner by ERα, through both the AF1 and AF2 domains. The pattern of ERα binding, histone H4 acetylation, and histone H3 cyclical methylation of lysine 9 was comparable to other estrogen-regulated promoters. Association of topoisomerase IIβ with the RIZ promoter 2 confirmed the transcriptional activation induced by estrogen. We hypothesize that RIZ2, acting as a negative regulator of RIZ1 function, mediates the proliferative effect of estrogen through regulation of survival and differentiation gene expression.
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Affiliation(s)
- Ciro Abbondanza
- Dipartimento di Patologia generale, Seconda Università degli studi di Napoli, Naples, Italy
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12
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Roy S, Jørgensen HG, Roy P, Abed El Baky M, Melo JV, Strathdee G, Holyoake TL, Bartholomew C. BCR-ABL1 tyrosine kinase sustained MECOM expression in chronic myeloid leukaemia. Br J Haematol 2012; 157:446-56. [PMID: 22372463 DOI: 10.1111/j.1365-2141.2012.09078.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2011] [Accepted: 02/01/2012] [Indexed: 01/21/2023]
Abstract
MECOM oncogene expression correlates with chronic myeloid leukaemia (CML) progression. Here we show that the knockdown of MECOM (E) and MECOM (ME) isoforms reduces cell division at low cell density, inhibits colony-forming cells by 34% and moderately reduces BCR-ABL1 mRNA and protein expression but not tyrosine kinase catalytic activity in K562 cells. We also show that both E and ME are expressed in CD34(+) selected cells of both CML chronic phase (CML-CP), and non-CML (normal) origin. Furthermore, MECOM mRNA and protein expression were repressed by imatinib mesylate treatment of CML-CP CD34(+) cells, K562 and KY01 cell lines whereas imatinib had no effect in non-CML BCR-ABL1 -ve CD34(+) cells. Together these results suggest that BCR-ABL1 tyrosine kinase catalytic activity regulates MECOM gene expression in CML-CP progenitor cells and that the BCR-ABL1 oncoprotein partially mediates its biological activity through MECOM. MECOM gene expression in CML-CP progenitor cells would provide an in vivo selective advantage, contributing to CML pathogenesis.
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Affiliation(s)
- Swagata Roy
- Department of Life Sciences, City Campus, Glasgow Caledonian University, Glasgow, UK
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13
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Khaenam P, Niibori A, Okada S, Jearanaikoon P, Araki N, Limpaiboon T. Contribution of RIZ1 to regulation of proliferation and migration of a liver fluke-related cholangiocarcinoma cell. Asian Pac J Cancer Prev 2012; 13:4007-4011. [PMID: 23098508 DOI: 10.7314/apjcp.2012.13.8.4007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
PURPOSE Retinoblastoma-interacting zinc finger gene (RIZ1) is a tumor suppressor gene which is highly inactivated by promoter hypermethylation in patients with liver fluke-related cholangiocarcinoma (CCA). Epigenetic aberration of this gene might withdraw the ability to restrain tumor cell proliferation and migration. We aimed to define the role of RIZ1 on cell proliferation and migration in CCA cell line. MATERIALS AND METHODS Small interference RNA (siRNA) was used to knock down the expression of RIZ1 in a CCA-derived cell line in which cell proliferation and cell migration were performed. RESULTS A predominant nuclear localization of RIZ1 was observed. Reduction of RIZ1 by siRNA augmented cell proliferation and migration. CONCLUSION The result suggested that RIZ1 might play a role in regulating cell proliferation and migration in CCA. Reduction of RIZ1 expression may aggravate the progression of CCA.
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Affiliation(s)
- Prasong Khaenam
- Department of Biomedical Sciences, Graduate School, Khon Kaen University, Khon Kaen, Thailand
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14
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Cheng HY, Gao Y, Lou G. DNA methylation of the RIZ1 tumor suppressor gene plays an important role in the tumorigenesis of cervical cancer. Eur J Med Res 2010; 15:20-4. [PMID: 20159667 PMCID: PMC3351843 DOI: 10.1186/2047-783x-15-1-20] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abtract
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Affiliation(s)
- H Y Cheng
- Department of Gynecologic Oncology, The Tumor Hospital of Harbin Medical University, Heilongjiang, 150081, China
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15
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Garriock HA, Kraft JB, Shyn SI, Peters EJ, Yokoyama JS, Jenkins GD, Reinalda MS, Slager SL, McGrath PJ, Hamilton SP. A genomewide association study of citalopram response in major depressive disorder. Biol Psychiatry 2010; 67:133-8. [PMID: 19846067 PMCID: PMC2794921 DOI: 10.1016/j.biopsych.2009.08.029] [Citation(s) in RCA: 224] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2009] [Revised: 08/20/2009] [Accepted: 08/21/2009] [Indexed: 10/20/2022]
Abstract
BACKGROUND Antidepressant response is likely influenced by genetic constitution, but the actual genes involved have yet to be determined. We have carried out a genomewide association study to determine whether common DNA variation influences antidepressant response. METHODS Our sample is derived from Level 1 participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, all treated with citalopram. Association for the response phenotype included 883 responders and 608 nonresponders. For the remission phenotype, 743 subjects that achieved remission were compared with 608 nonresponders. We used a subset of single nucleotide polymorphisms (SNPs; n = 430,198) from the Affymetrix 500K and 5.0 Human SNP Arrays, and association analysis was carried out after correcting for population stratification. RESULTS We identified three SNPs associated with response with p values less than 1 x 10(-5) near the UBE3C gene (rs6966038, p = 4.65 x 10(-7)), another 100 kb away from BMP7 (rs6127921, p = 3.45 x 10(-6)), and a third that is intronic in the RORA gene (rs809736, p = 8.19 x 10(-6)). These same SNPs were also associated with remission. Thirty-nine additional SNPs are of interest with p values < or = .0001 for the response and remission phenotypes. CONCLUSIONS Although the findings reported here do not meet a genomewide threshold for significance, the regions identified from this study provide targets for independent replication and novel pathways to investigate mechanisms of antidepressant response. This study was not placebo controlled, making it possible that we are also observing associations to nonspecific aspects of drug treatment of depression.
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Affiliation(s)
- Holly A. Garriock
- Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, CA
| | - Jeffrey B. Kraft
- Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, CA
| | - Stanley I. Shyn
- Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, CA
| | - Eric J. Peters
- Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, CA
| | - Jennifer S. Yokoyama
- Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, CA
| | | | - Megan S. Reinalda
- Department of Health Sciences Research, Mayo Clinic College of Medicine
| | - Susan L. Slager
- Department of Health Sciences Research, Mayo Clinic College of Medicine
| | - Patrick J. McGrath
- Department of Psychiatry, Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute
| | - Steven P. Hamilton
- Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, CA,corresponding author Steven P. Hamilton, MD, PhD, Carol Cochran Schaffner Endowed Chair in Mental Health, University of California, San Francisco, Department of Psychiatry, 401 Parnassus Ave, Box NGL-0984, San Francisco, CA, 94143-0984,
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16
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Rossi V, Staibano S, Abbondanza C, Pasquali D, De Rosa C, Mascolo M, Bellastella G, Visconti D, De Bellis A, Moncharmont B, De Rosa G, Puca GA, Bellastella A, Sinisi AA. Expression of RIZ1 protein (Retinoblastoma-interacting zinc-finger protein 1) in prostate cancer epithelial cells changes with cancer grade progression and is modulated in vitro by DHT and E2. J Cell Physiol 2009; 221:771-7. [PMID: 19746436 DOI: 10.1002/jcp.21920] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The nuclear protein methyl-transferase Retinoblastoma-interacting zinc-finger protein 1 (RIZ1) is considered to be a downstream effector of estrogen action in target tissues. Silencing of RIZ1 expression is common in many tumors. We analyzed RIZ1 expression in normal and malignant prostate tissue and evaluated whether estradiol (E2) or dihydrotestosterone (DHT) treatment modulated RIZ1 in cultured prostate epithelial cells (PEC). Moreover, we studied the possible involvement of RIZ1 in estrogen action on the EPN prostate cell line, constitutively expressing both estrogen receptor (ER)-alpha and beta. RIZ1 protein, found in the nucleus of normal PECs by immunohistochemistry, was progressively lost in cancer tissues as the Gleason score increased and was only detected in the cytoplasmic compartment. RIZ1 transcript levels, as assayed by semi-quantitative RT-PCR in primary PEC cultures, were significantly reduced in cancer cells (P < 0.05). In EPN DHT treatment significantly increased RIZ1 transcript and protein levels (P < 0.05); E2 induced a reduction of S phase without significant changes of RIZ1 expression. In E2-treated EPN cell extracts RIZ co-immunoprecipitated with ERbeta and ERalpha. Our data demonstrate that RIZ1 is expressed in normal PECs and down-regulated in cancer cells, with a switch of its sub-cellular localization from the nucleus to the cytoplasm upon cancer grade progression. RIZ1 expression levels in the PECs were modulated by DHT or E2 treatment in vitro. Furthermore, the E2 effects on ER-expressing prostate cells involve RIZ1, which confirms a possible role for ER-mediated pathways in a non-classic E(2)-target tissue.
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Affiliation(s)
- Valentina Rossi
- Dipartimento di Internistica Clinica e Sperimentale, Sezione di Endocrinologia, Seconda Università degli Studi di Napoli, Napoli, Italy
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17
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Stolk L, van Meurs JBJ, Arp PP, Hofman A, Pols HAP, Uitterlinden AG. The RIZ Pro704 insertion-deletion polymorphism, bone mineral density and fracture risk: the Rotterdam study. Bone 2008; 42:286-93. [PMID: 18037365 DOI: 10.1016/j.bone.2007.10.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2007] [Revised: 09/14/2007] [Accepted: 10/02/2007] [Indexed: 11/25/2022]
Abstract
Estrogens play a major role in the maintenance of bone and bone strength, and they exert their effects via estrogen receptors. Recently, an estrogen receptor alpha (ESR1) specific co-activator, retinoblastoma-interacting zinc-finger protein (RIZ1, 1p36), was shown to strongly enhance ESR1 function in vitro. The same study showed that a Proline insertion-deletion polymorphism at amino acid position 704 (Pro704 ins/del) in the RIZ1 gene was associated with heel BMD in young Swedish women. We tested the relation between the RIZ1 Pro704 ins/del polymorphism and BMD and fracture risk in Caucasian elderly men and women of the Rotterdam study. We also examined whether estradiol levels (measured in a subset) or genetic variation in ESR1 influenced this relation. In 2424 men and 3517 women from the Rotterdam study, RIZ1 genotypes were determined and associations with BMD (lumbar spine and femoral neck) and fracture risk were analysed. We recorded 374 vertebral fractures at baseline and during 6.4+/-0.4 (SD) years of follow-up, and 1219 incident non-vertebral fractures during 7.4+/-3.3 (SD) years of follow-up. The allele frequency of the Pro704 insertion was 41%, the genotype distribution was in Hardy-Weinberg Equilibrium (P=0.94). We found no association of this polymorphism with BMD or fracture risk. Stratification for gender, estradiol levels or interaction with ESR1 risk haplotype did not change these results. In conclusion, in this large study we observed no association of the RIZ1 Pro704 insertion-deletion polymorphism with BMD or fracture risk. This suggests this polymorphism to play a minor role, if any, as a genetic determinant of osteoporosis in elderly subjects.
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Affiliation(s)
- Lisette Stolk
- Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
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18
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Abstract
Leukemia is a group of monoclonal diseases that arise from hematopoietic stem and progenitor cells in the bone marrow or other hematopoietic organs. Retroviral infections are one of the major events leading to leukemogenesis in mice, because retroviruses can induce hematopoietic disease via the insertional mutagenesis of oncogenes; therefore, the cloning of viral-integration sites in murine leukemia has provided valuable molecular tags for oncogene discovery. Transcription of the murine gene ecotropic viral-integration site 1 (Evi1) is activated by nearby viral integration. In humans, the Evi1 homologue EVI1 is activated by chromosomal translocations. This review discusses the roles of the overexpression of EVI1/MEL1 gene family members in leukemogenesis, the relationships of various translocations in EVI1 overexpression, and the importance of PR domains in tumor suppression and oncogenesis. The functions of EVI1/MEL1 members as transcription factors and the concept of EVI1-positive leukemia as a stem cell disease are also reviewed.
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Affiliation(s)
- Kazuhiro Morishita
- Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, Miyazaki, Japan.
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McGilvray R, Walker M, Bartholomew C. UXT interacts with the transcriptional repressor protein EVI1 and suppresses cell transformation. FEBS J 2007; 274:3960-71. [PMID: 17635584 DOI: 10.1111/j.1742-4658.2007.05928.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The EVI1 transcriptional repressor is critical to the normal development of a variety of tissues and participates in the progression of acute myeloid leukaemias. The repressor domain (Rp) was used to screen an adult human kidney yeast two-hybrid library and a novel binding partner designated ubiquitously expressed transcript (UXT) was isolated. Enforced expression of UXT in Evi1-expressing Rat1 fibroblasts suppresses cell transformation and UXT may therefore be a negative regulator of Evi1 biological activity. The Rp-binding site for UXT was determined and non-UXT-binding Evi1 mutants (Evi1Delta706-707) were developed which retain the ability to bind the corepressor mCtBP2. Evi1Delta706-707 transforms Rat1 fibroblasts, showing that the interaction is not essential for Evi1-mediated cell transformation. However, Evi1Delta706-707 produces an increased proportion of large colonies relative to wild-type, showing that endogenous UXT has an inhibitory effect on Evi1 biological activity. Exogenous UXT still suppresses Evi1Delta706-707-mediated cell transformation, indicating that it inhibits cell proliferation and/or survival by both Evi1-dependent and Evi1-independent mechanisms. These observations are consistent with the growth-suppressive function attributed to UXT in human prostate cancer. Our results show that UXT suppresses cell transformation and might mediate this function by interaction and inhibition of the biological activity of cell proliferation and survival stimulatory factors like Evi1.
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Affiliation(s)
- Roger McGilvray
- Department of Biological & Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK
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20
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Alzuherri H, McGilvray R, Kilbey A, Bartholomew C. Conservation and expression of a novel alternatively spliced Evi1 exon. Gene 2006; 384:154-62. [PMID: 17014970 DOI: 10.1016/j.gene.2006.07.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2006] [Revised: 07/20/2006] [Accepted: 07/25/2006] [Indexed: 11/19/2022]
Abstract
The Evi1 transcriptional repressor protein is expressed in a developmentally regulated manner, is essential for normal development, participates in regulating cell proliferation and differentiation of cells of haemopoietic and neuronal origin and contributes to the progression of leukaemia. In this report we describe a new murine Evi1 gene transcript (Delta105) that contains two alternatively spliced regions encoding a 9 amino acid insertion (Rp+9) within the repressor domain (Rp) and a 105 amino acid C-terminal truncation. Abundant levels of the 105 amino acid truncated protein are observed in murine leukaemia cells. The combined primary sequence alterations do not affect the DNA binding, transcriptional repressor or CtBP2 protein binding properties of Evi1 but they do reduce its transforming and cell proliferation stimulating activities. Reduced transforming activity is most likely due to the C-terminal truncation as the activity of Evi1 containing either Rp or Rp+9 is indistinguishable. Both isoforms exist in all murine tissues and cell lines examined. However, only the Rp+9 alternative splice variant is also found in humans and other vertebrates. Murine and human forms of Evi1 with Rp or Rp+9 exist. The additional 9 amino acids are encoded by a conserved 27 nucleotide exon, the overall structural organisation of the gene being preserved in the two species. The function of the Rp+9 and Delta105 splice variants is unknown although the conservation of Rp+9 throughout evolution in vertebrate species suggests it is essential to the broad spectrum of biological activities attributed to this developmentally essential protein.
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Affiliation(s)
- Hadi Alzuherri
- Glasgow Caledonian University, Department of Biological and Biomedical Sciences, City Campus Cowcaddens Road Glasgow, G4 OBA, United Kingdom
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21
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Chambery A, Farina A, Di Maro A, Rossi M, Abbondanza C, Moncharmont B, Malorni L, Cacace G, Pocsfalvi G, Malorni A, Parente A. Proteomic analysis of MCF-7 cell lines expressing the zinc-finger or the proline-rich domain of retinoblastoma-interacting-zinc-finger protein. J Proteome Res 2006; 5:1176-85. [PMID: 16674107 DOI: 10.1021/pr0504743] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
To identify a growth-promoting activity related to retinoblastoma-interacting-zinc-finger (RIZ) protein, differential protein expression of MCF-7 cell lines expressing the zinc-finger or the proline-rich domain of RIZ protein was analyzed by a robust bottom-up mass-spectrometry proteomic approach. Spots corresponding to qualitative and quantitative differences in protein expression have been selected and identified. Some of these proteins have been previously reported as being associated with different types of carcinomas or involved in cell proliferation and differentiation. Knowledge of specific differentially expressed proteins by MCF-7-derived cell lines expressing RIZ different domains will provide the basis for identifying a growth-promoting activity related to RIZ gene products.
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Affiliation(s)
- Angela Chambery
- Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, I-81100 Caserta, Italy
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22
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Davis CA, Haberland M, Arnold MA, Sutherland LB, McDonald OG, Richardson JA, Childs G, Harris S, Owens GK, Olson EN. PRISM/PRDM6, a transcriptional repressor that promotes the proliferative gene program in smooth muscle cells. Mol Cell Biol 2006; 26:2626-36. [PMID: 16537907 PMCID: PMC1430312 DOI: 10.1128/mcb.26.7.2626-2636.2006] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Smooth muscle cells (SMCs) display remarkable phenotypic diversity and plasticity and can readily switch between proliferative and differentiated states in response to extracellular cues. In an effort to identify novel transcriptional regulators of smooth muscle phenotypes, we compared the gene expression profiles of arterial and venous SMCs by microarray-based transcriptional profiling. Among numerous genes displaying distinct expression patterns in these two SMC types, we discovered an expressed sequence tag encoding a previously uncharacterized zinc finger protein belonging to the PRDM (PRDI-BF1 and RIZ homology domain) family of chromatin-remodeling proteins and named it PRISM (PR domain in smooth muscle). PRISM is expressed in a variety of smooth muscle-containing tissues and displays especially robust expression in the cardiac outflow tract and descending aorta during embryogenesis. PRISM is localized to the nucleus and contains an amino-terminal PR domain and four Krüppel-like zinc fingers at the carboxy terminus. We show that PRISM acts as a transcriptional repressor by interacting with class I histone deacetylases and the G9a histone methyltransferase, thereby identifying PRISM as a novel SMC-restricted epigenetic regulator. Overexpression of PRISM in cultured primary SMCs induces genes associated with the proliferative smooth muscle phenotype while repressing regulators of differentiation, including myocardin and GATA-6. Conversely, small interfering RNA-mediated knockdown of PRISM slows cell growth and induces myocardin, GATA-6, and markers of SMC differentiation. We conclude that PRISM acts as a novel epigenetic regulator of SMC phenotypic plasticity by suppressing differentiation and maintaining the proliferative potential of vascular SMCs.
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Affiliation(s)
- Christopher A Davis
- Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9148, USA
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Rossi M, Abbondanza C, D'Arcangelo A, Gazzerro P, Medici N, Moncharmont B, Puca GA. The Zn-finger domain of RIZ protein promotes MCF-7 cell proliferation. Cancer Lett 2004; 215:229-37. [PMID: 15488642 DOI: 10.1016/j.canlet.2004.05.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2004] [Revised: 05/18/2004] [Accepted: 05/19/2004] [Indexed: 11/26/2022]
Abstract
In order to understand the oncogenic properties of retinoblastoma-interacting zinc-finger (RIZ) gene products, we produced an MCF-7-derived cell line expressing a fusion protein containing the zinc-finger (aa 359-497) domain of RIZ protein (MCF-7/znf). The Zn-finger domain contains three of the eight putative Zn-finger motifs and is located in proximity of the E1A-like domain containing the Rb protein-binding motif. The MCF-7/znf cells showed a higher growth rate than the parental or the control cell lines, both in hormone-deprived conditions or upon estrogen stimulation. Furthermore, they were less sensitive to the growth inhibitory effect of anti-estrogens and showed a higher level of expression of cyclin D1 and A. The expressed Zn-finger domain recombinant product was localized in the nucleus and in the nucleoli and its expression modified the pattern of actin staining in the cytoplasm. In conclusion the presented results indicated that the Zn-finger domain could be endowed with the putative oncogenic activity of RIZ2 gene product.
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Affiliation(s)
- Mariangela Rossi
- Dipartimento di Patologia generale, Facoltà di Medicina e Chirurgia, Seconda Università degli studi di Napoli, Via Luigi de Crecchio, 7, Naples I-80138, Italy
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Pan KF, Lu YY, Liu WG, Zhang L, You WC. Detection of frameshift mutations of RIZ in gastric cancers with microsatellite instability. World J Gastroenterol 2004; 10:2719-22. [PMID: 15309726 PMCID: PMC4572200 DOI: 10.3748/wjg.v10.i18.2719] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To study the frameshift mutations of the retinoblastoma protein-interacting zinc finger gene RIZ in gastric cancer with microsatellite instability, and to identify two coding polyadenosine tracts of RIZ.
METHODS: Frameshift mutations at (A)8 and (A)9 tracts of RIZ were detected in 70 human gastric cancer (HGC) specimens by DHPLC and DNA sequencing. Microsatellite instability (MSI) status was assessed by two mononucleotide markers, BAT26 and BAT25, by means of denaturing high-performance liquid chromatography (DHPLC).
RESULTS: In 70 HGC samples, 8 (11.4%) were found positive for instabilities at BAT26 and BAT25. In 7 of the 8 cases with instabilities at both BAT26 and BAT25 (MSI-H), 1 was unstable at BAT26 but stable at BAT25. Frameshift mutations were identified in 4 (57.1%) of the 7 samples with MSI-H in the (A)9 tract of RIZ without mutations in the (A)8 tract. In contrast, frameshift mutations were found in neither of the polyadenosine tracts in 63 samples of MSI-L or MSI stable tumors. Pro704 LOH detection in 4 cases with frameshift mutations did not find LOH in these cases.
CONCLUSION: Frameshift mutations of RIZ may play an important role in gastric cancers with MSI.
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Affiliation(s)
- Kai-Feng Pan
- Department of Cancer Epidemiology, Peking University School of Oncology, Beijing Institute for Cancer Research, Beijing Cancer Hospital, Beijing 100034, China
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Abstract
AIM: To analyze the genetic and epigenetic alterations of RUNX3 gene, a potential putative tumor suppressor gene, in hepatocellular carcinoma (HCC).
METHODS: PCR-based loss of heterozygosity (LOH) detection, analysis of mutation with PCR-single strand conformational polymorphism (SSCP) and sequencing, and methylation study with methylation specific PCR (MSP) were performed on RUNX3 gene in a series of 62 HCCs along with their matched normal tissues.
RESULTS: Mutation of RUNX3 gene was not found, but one single nucleotide polymorphism with T to A transversion at the second nucleotide of the 18th condon was found. Nine of 26 informative cases (34.6%) showed allelic loss on the polymorphic site and 30 cases (48.4%) revealed hypermethylation of RUNX3 gene in promoter CpG islands. Furthermore, of the 9 cases with LOH, 8 (88.9%) also had hypermethylation.
CONCLUSION: Our findings indicate that inactivation of RUNX3 gene through allelic loss and promoter hypermethylation might be one of the major mechanisms in hepatocellualr carcinogenesis.
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Affiliation(s)
- Wen-Hua Xiao
- Department of Oncology, 304th Hospital of PLA, Beijing 100037, China.
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Coupland LA, Jammu V, Pidcock ME. Partial deletion of chromosome 1 in a case of acute myelocytic leukemia. CANCER GENETICS AND CYTOGENETICS 2002; 139:60-2. [PMID: 12547161 DOI: 10.1016/s0165-4608(02)00597-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Acute myelocytic leukemia (AML) is a malignant disease characterized by the proliferation of immature myelocytic precursor cells causing the disruption of normal bone marrow function. Many chromosomal aberrations have been described in AML including translocations, inversions, deletions, and additions. Here we describe a novel deletion of chromosome 1, del(1)(p34p36) in a case of AML, French-American-British classification M1, in a previously healthy 33-year-old male. This isolated cytogenetic abnormality occurred in 33% of the myeloblasts examined at diagnosis. Subsequent cytogenetic analyses conducted on marrow following induction and consolidation therapy demonstrated a normal male karyotype in all cells examined. The patient remains in clinical and hematological remission 22 months following diagnosis. The presence of 1p abnormalities in AML and other malignancies is reviewed, as are candidate tumor suppressor genes in the 1p34 approximately p36 region. The implications of chromosome 1p abnormalities on clinical outcome are also discussed.
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Affiliation(s)
- L A Coupland
- Department of Clinical Haematology, The Canberra Hospital, Garran, Australia.
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Schneider R, Bannister AJ, Kouzarides T. Unsafe SETs: histone lysine methyltransferases and cancer. Trends Biochem Sci 2002; 27:396-402. [PMID: 12151224 DOI: 10.1016/s0968-0004(02)02141-2] [Citation(s) in RCA: 229] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Enzymes that covalently modify histones control many cellular processes by affecting gene expression. A new class of these enzymes is the histone lysine methyltransferase family, whose catalytic activity lies within a conserved domain, the SET domain. This article surveys the evidence for a connection between SET-domain-containing proteins and cancer. It proposes that deregulation of SET-domain function has an important role in carcinogenesis.
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Affiliation(s)
- Robert Schneider
- Wellcome/Cancer Research UK Institute and Department of Pathology, Tennis Court Road, Cambridge, UK CB2 1QR
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Schäfer U, Schneider A, Neugebauer E. Identification of a nitric oxide-regulated zinc finger containing transcription factor using motif-directed differential display. BIOCHIMICA ET BIOPHYSICA ACTA 2000; 1494:269-76. [PMID: 11121585 DOI: 10.1016/s0167-4781(00)00249-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
We report here the isolation of human zinc finger 2 (HZF2), a putative zinc-finger transcription factor, by motif-directed differential display of mRNA extracted from histamine-stimulated human vein endothelial cells. The expression of HZF2 mRNA in venous endothelial cells was verified by Northern blot analysis, which also revealed an enrichment of HZF2 mRNA in lymphocytes and monocytes. Histamine induced a time- and concentration-dependent upregulation of HZF2 level with a 6-fold peak increase of mRNA at 30 min. HZF2 upregulation was abolished by different NOS isozyme inhibitors. Guanylate cyclase inhibition resulted in a significant decrease of HZF2 expression. These observations indicate HZF2 as a potentially interesting new target for studies concerning rapid NO-mediated gene regulation.
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Affiliation(s)
- U Schäfer
- Biochemical and Experimental Division, II. Department of Surgery, University of Cologne, Ostmerheimer Str. 200, 51109 Cologne, Germany.
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Yang XH, Huang S. PFM1 (PRDM4), a new member of the PR-domain family, maps to a tumor suppressor locus on human chromosome 12q23-q24.1. Genomics 1999; 61:319-25. [PMID: 10552934 DOI: 10.1006/geno.1999.5967] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The PR domain, first noted as the PRDI-BF1 (HGMW-approved symbol PRDM1) and RIZ (HGMW-approved symbol PRDM2) homologous region, defines a small family of transcription factors involved in cell differentiation and tumorigenesis. The shared role of this family in human cancer raises considerable interest in identifying novel members of this family as candidate cancer genes. This paper describes a new human PR family member, designated PFM1 (HGMW-approved symbol PRDM4). A full-length PFM1 cDNA of 3902 nucleotides has been isolated based on its homology to the PR domain. It encodes an open reading frame of 796 amino acids and contains a PR domain in the middle region and six zinc finger motifs at the carboxyl-terminus. Several PFM1 mRNA species of different lengths were detected by Northern blot analysis, one species of which lacked the amino-terminal region of PFM1 and part of the PR domain. The major PFM1 mRNA species of approximately 4.6 kb was widely expressed but more abundant in ovary, testis, pancreas, brain, heart, and prostate. PFM1 mRNA levels were highly elevated in PC12 cells treated with NGF, suggesting a role for PFM1 in the NGF signal transduction pathway. STS marker and radiation hybrid analyses mapped PFM1 to human chromosome 12q23-q24.1, a region thought to harbor tumor suppressor genes for ovarian, gastric, and pancreatic cancers. These results suggest a role for PFM1 in cell differentiation and tumor suppression, remarkably consistent with the known functions of the PR-domain family.
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Affiliation(s)
- X H Yang
- Program in Oncogenes and Tumor Suppressor Genes, The Burnham Institute, La Jolla, California, 92037, USA
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