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Torun V, Degerli E, Cansaran-Duman D. Revealing the Molecular Signatures of miR-185-5p on Breast Cancer Cells Using Proteomic Analysis. Protein Pept Lett 2024; 31:681-695. [PMID: 39323334 DOI: 10.2174/0109298665322427240906060626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 07/28/2024] [Accepted: 08/20/2024] [Indexed: 09/27/2024]
Abstract
BACKGROUND Breast cancer is a heterogeneous type of disease in which genetic and environmental factors play a crucial role. There are several types of treatment for breast cancer (BC) patients. However, the biggest problem in the treatment of breast cancer is the resistance that occurs during the treatment with chemotherapeutic agents. Usnic acid, a secondary metabolite of lichen, has been identified as a drug candidate molecule in cancer treatment. The determination of miRNA target proteins is essential for the understanding of molecular mechanisms of miRNA-related tumorigenesis. OBJECTIVES We determined that mir-185-5p has therapeutic potential at the miRNA level by applying usnic acid to BT-474 breast cancer cells in a previous study. Herein, we aimed to investigate the molecular mechanisms of miR-185-5p on BT-474 breast cancer cells using a proteomics approach. We explored the changes in the protein expression level of BT-474 breast cancer cells in response to the up-regulation of miR-185-5p after applying usnic acid as a novel candidate anti-- cancer drug molecule. METHODS We performed quantitative proteome analysis based on an LC-MS/MS assay, which was validated by western blotting. The differentially expressed proteins were analyzed using the latest data available in bioinformatics tools. The up-regulated expression of YWHAE, Cathepsin D, and the down-regulated levels of PAK-1 were demonstrated by western blot assay. RESULTS According to the results, 86 proteins showing >2-fold change were identified as differentially expressed between breast cancer and normal breast epithelial cells. The apoptosis pathway was the main clade containing most of the proteins regulated by miR-185-5p. The results indicate that miR-185-5p modulates apoptosis signaling pathways in BT-474 breast cancer cells. Breast cancer inhibition due to increased expression of YWHAE, Cathepsin D, and decreased expression of PAK-1 is likely to be mediated by inducing miR-185-5p mediated apoptosis. CONCLUSION In this study, the identification of miR-185-5p protein targets demonstrated the potential for the development of targeted therapy and the development of miRNA-based therapeutics and presented it as a biomarker for breast cancer diagnosis, prognosis, and treatment response. In this regard, proteome analyses provided an understanding of the molecular mechanism underlying the effect of miR-185-5p on breast cancer.
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Affiliation(s)
- Vildan Torun
- Ankara University, Biotechnology Institute, Keçiören, Ankara, Turkey
| | - Elif Degerli
- Ankara University, Biotechnology Institute, Keçiören, Ankara, Turkey
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Ray S, Chaturvedi NK, Bhakat KK, Rizzino A, Mahapatra S. Subgroup-Specific Diagnostic, Prognostic, and Predictive Markers Influencing Pediatric Medulloblastoma Treatment. Diagnostics (Basel) 2021; 12:diagnostics12010061. [PMID: 35054230 PMCID: PMC8774967 DOI: 10.3390/diagnostics12010061] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/11/2021] [Accepted: 12/18/2021] [Indexed: 12/24/2022] Open
Abstract
Medulloblastoma (MB) is the most common malignant central nervous system tumor in pediatric patients. Mainstay of therapy remains surgical resection followed by craniospinal radiation and chemotherapy, although limitations to this therapy are applied in the youngest patients. Clinically, tumors are divided into average and high-risk status on the basis of age, metastasis at diagnosis, and extent of surgical resection. However, technological advances in high-throughput screening have facilitated the analysis of large transcriptomic datasets that have been used to generate the current classification system, dividing patients into four primary subgroups, i.e., WNT (wingless), SHH (sonic hedgehog), and the non-SHH/WNT subgroups 3 and 4. Each subgroup can further be subdivided on the basis of a combination of cytogenetic and epigenetic events, some in distinct signaling pathways, that activate specific phenotypes impacting patient prognosis. Here, we delve deeper into the genetic basis for each subgroup by reviewing the extent of cytogenetic events in key genes that trigger neoplastic transformation or that exhibit oncogenic properties. Each of these discussions is further centered on how these genetic aberrations can be exploited to generate novel targeted therapeutics for each subgroup along with a discussion on challenges that are currently faced in generating said therapies. Our future hope is that through better understanding of subgroup-specific cytogenetic events, the field may improve diagnosis, prognosis, and treatment to improve overall quality of life for these patients.
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Affiliation(s)
- Sutapa Ray
- Department of Pediatrics, University of Nebraska Medical Center, 601 S Saddle Creek Road, Omaha, NE 68198, USA; (S.R.); (N.K.C.)
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
| | - Nagendra K. Chaturvedi
- Department of Pediatrics, University of Nebraska Medical Center, 601 S Saddle Creek Road, Omaha, NE 68198, USA; (S.R.); (N.K.C.)
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
| | - Kishor K. Bhakat
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Angie Rizzino
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
- Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sidharth Mahapatra
- Department of Pediatrics, University of Nebraska Medical Center, 601 S Saddle Creek Road, Omaha, NE 68198, USA; (S.R.); (N.K.C.)
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Correspondence: ; Tel.: +1-(402)-599-7754
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3
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Perumal N, Kanchan RK, Doss D, Bastola N, Atri P, Chirravuri-Venkata R, Thapa I, Vengoji R, Maurya SK, Klinkebiel D, Talmon GA, Nasser MW, Batra SK, Mahapatra S. MiR-212-3p functions as a tumor suppressor gene in group 3 medulloblastoma via targeting nuclear factor I/B (NFIB). Acta Neuropathol Commun 2021; 9:195. [PMID: 34922631 PMCID: PMC8684142 DOI: 10.1186/s40478-021-01299-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 12/01/2021] [Indexed: 12/30/2022] Open
Abstract
Haploinsufficiency of chromosome 17p and c-Myc amplification distinguish group 3 medulloblastomas which are associated with early metastasis, rapid recurrence, and swift mortality. Tumor suppressor genes on this locus have not been adequately characterized. We elucidated the role of miR-212-3p in the pathophysiology of group 3 tumors. First, we learned that miR-212-3p undergoes epigenetic silencing by histone modifications in group 3 tumors. Restoring its expression reduced cancer cell proliferation, migration, colony formation, and wound healing in vitro and attenuated tumor burden and improved survival in vivo. MiR-212-3p also triggered c-Myc destabilization and degradation, leading to elevated apoptosis. We then isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors and associated with poor survival. NFIB silencing reduced cancer cell proliferation, migration, and invasion. Concurrently, reduced medullosphere formation and stem cell markers (Nanog, Oct4, Sox2, CD133) were noted. These results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and identify a novel oncogenic target implicated in metastasis and tumor recurrence.
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Affiliation(s)
- Naveenkumar Perumal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ranjana K Kanchan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - David Doss
- Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, 68124, USA
| | - Noah Bastola
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | | | - Ishwor Thapa
- School of Interdisciplinary Informatics, University of Nebraska at Omaha, Omaha, NE, 68182, USA
| | - Raghupathy Vengoji
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Shailendra K Maurya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - David Klinkebiel
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Geoffrey A Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mohd W Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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4
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Liaño-Pons J, Arsenian-Henriksson M, León J. The Multiple Faces of MNT and Its Role as a MYC Modulator. Cancers (Basel) 2021; 13:4682. [PMID: 34572909 PMCID: PMC8465425 DOI: 10.3390/cancers13184682] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 12/29/2022] Open
Abstract
MNT is a crucial modulator of MYC, controls several cellular functions, and is activated in most human cancers. It is the largest, most divergent, and most ubiquitously expressed protein of the MXD family. MNT was first described as a MYC antagonist and tumor suppressor. Indeed, 10% of human tumors present deletions of one MNT allele. However, some reports show that MNT functions in cooperation with MYC by maintaining cell proliferation, promoting tumor cell survival, and supporting MYC-driven tumorigenesis in cellular and animal models. Although MAX was originally considered MNT's obligate partner, our recent findings demonstrate that MNT also works independently. MNT forms homodimers and interacts with proteins both outside and inside of the proximal MYC network. These complexes are involved in a wide array of cellular processes, from transcriptional repression via SIN3 to the modulation of metabolism through MLX as well as immunity and apoptosis via REL. In this review, we discuss the present knowledge of MNT with a special focus on its interactome, which sheds light on the complex and essential role of MNT in cell biology.
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Affiliation(s)
- Judit Liaño-Pons
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 65 Stockholm, Sweden;
| | - Marie Arsenian-Henriksson
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, SE-171 65 Stockholm, Sweden;
| | - Javier León
- Departmento de Biología Molecular and Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Universidad de Cantabria-CSIC, 39011 Santander, Spain;
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5
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Shostak A, Schermann G, Diernfellner A, Brunner M. MXD/MIZ1 transcription regulatory complexes activate the expression of MYC-repressed genes. FEBS Lett 2021; 595:1639-1655. [PMID: 33914337 DOI: 10.1002/1873-3468.14097] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 03/31/2021] [Accepted: 04/01/2021] [Indexed: 12/27/2022]
Abstract
MXDs are transcription repressors that antagonize MYC-mediated gene activation. MYC, when associated with MIZ1, acts also as a repressor of a subset of genes, including p15 and p21. A role for MXDs in regulation of MYC-repressed genes is not known. We report that MXDs activate transcription of p15 and p21 in U2OS cells. This activation required DNA binding by MXDs and their interaction with MIZ1. MXD mutants deficient in MIZ1 binding interacted with the MYC-binding partner MAX and were active as repressors of MYC-activated genes but failed to activate MYC-repressed genes. Mutant MXDs with reduced DNA-binding affinity interacted with MAX and MIZ1 but neither repressed nor activated transcription. Our data show that MXDs and MYC have a reciprocally antagonistic potential to regulate transcription of target genes.
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6
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Liaño-Pons J, Lafita-Navarro MC, García-Gaipo L, Colomer C, Rodríguez J, von Kriegsheim A, Hurlin PJ, Ourique F, Delgado MD, Bigas A, Espinosa L, León J. A novel role of MNT as a negative regulator of REL and the NF-κB pathway. Oncogenesis 2021; 10:5. [PMID: 33419981 PMCID: PMC7794610 DOI: 10.1038/s41389-020-00298-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 11/20/2020] [Accepted: 12/02/2020] [Indexed: 01/29/2023] Open
Abstract
MNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix-loop-helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it. However, the molecular interactions involving MNT as a transcriptional regulator beyond the binding to MAX remain unexplored. Here we demonstrate a novel MAX-independent protein interaction between MNT and REL, the oncogenic member of the NF-κB family. REL participates in important biological processes and it is altered in a variety of tumors. REL is a transcription factor that remains inactive in the cytoplasm in an inhibitory complex with IκB and translocates to the nucleus when the NF-κB pathway is activated. In the present manuscript, we show that MNT knockdown triggers REL translocation into the nucleus and thus the activation of the NF-κB pathway. Meanwhile, MNT overexpression results in the repression of IκBα, a bona fide REL target. Both MNT and REL bind to the IκBα gene on the first exon, suggesting its regulation as an MNT-REL complex. Altogether our data indicate that MNT acts as a repressor of the NF-κB pathway by two mechanisms: (1) retention of REL in the cytoplasm by MNT interaction, and (2) MNT-driven repression of REL-target genes through an MNT-REL complex. These results widen our knowledge about MNT biological roles and reveal a novel connection between the MYC/MXD and NF-κB pathways, two of the most prominent pathways in cancer.
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Affiliation(s)
- Judit Liaño-Pons
- Departmento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum B7, Karolinska Institutet, Stockholm, Sweden
| | - M Carmen Lafita-Navarro
- Departmento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain
- Department of Cell Biology UT Southwestern Medical Center, Dallas, TX, USA
| | - Lorena García-Gaipo
- Departmento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain
| | - Carlota Colomer
- Cancer Research Program, Institut Hospital del Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain
| | - Javier Rodríguez
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
| | - Alex von Kriegsheim
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
- Edinburgh Cancer Research Center, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Peter J Hurlin
- Shriners Hospitals for Children Research Center, Department of Cell, Developmental and Cancer Biology and Department of Orthopaedics and Rehabilitation, Oregon Health and Science University, Portland, OR, USA
| | - Fabiana Ourique
- Departmento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain
- Dept. of Biochemistry, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil
| | - M Dolores Delgado
- Departmento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain
| | - Anna Bigas
- Cancer Research Program, Institut Hospital del Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain
| | - Lluis Espinosa
- Cancer Research Program, Institut Hospital del Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain
| | - Javier León
- Departmento de Biología Molecular, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain.
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Kanchan RK, Perumal N, Atri P, Chirravuri Venkata R, Thapa I, Klinkebiel DL, Donson AM, Perry D, Punsoni M, Talmon GA, Coulter DW, Boue' DR, Snuderl M, Nasser MW, Batra SK, Vibhakar R, Mahapatra S. MiR-1253 exerts tumor-suppressive effects in medulloblastoma via inhibition of CDK6 and CD276 (B7-H3). Brain Pathol 2020; 30:732-745. [PMID: 32145124 PMCID: PMC7383594 DOI: 10.1111/bpa.12829] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 02/04/2020] [Accepted: 02/25/2020] [Indexed: 12/21/2022] Open
Abstract
Of the four primary subgroups of medulloblastoma, the most frequent cytogenetic abnormality, i17q, distinguishes Groups 3 and 4 which carry the highest mortality; haploinsufficiency of 17p13.3 is a marker for particularly poor prognosis. At the terminal end of this locus lies miR-1253, a brain-enriched microRNA that regulates bone morphogenic proteins during cerebellar development. We hypothesized miR-1253 confers novel tumor-suppressive properties in medulloblastoma. Using two different cohorts of medulloblastoma samples, we first studied the expression and methylation profiles of miR-1253. We then explored the anti-tumorigenic properties of miR-1253, in parallel with a biochemical analysis of apoptosis and proliferation, and isolated oncogenic targets using high-throughput screening. Deregulation of miR-1253 expression was noted, both in medulloblastoma clinical samples and cell lines, by epigenetic silencing via hypermethylation; specific de-methylation of miR-1253 not only resulted in rapid recovery of expression but also a sharp decline in tumor cell proliferation and target gene expression. Expression restoration also led to a reduction in tumor cell virulence, concomitant with activation of apoptotic pathways, cell cycle arrest and reduction of markers of proliferation. We identified two oncogenic targets of miR-1253, CDK6 and CD276, whose silencing replicated the negative trophic effects of miR-1253. These data reveal novel tumor-suppressive properties for miR-1253, i.e., (i) loss of expression via epigenetic silencing; (ii) negative trophic effects on tumor aggressiveness; and (iii) downregulation of oncogenic targets.
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Affiliation(s)
- Ranjana K Kanchan
- Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE
| | - Naveenkumar Perumal
- Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE
| | - Pranita Atri
- Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE
| | | | - Ishwor Thapa
- School of Interdisciplinary Informatics, University of Nebraska at Omaha, Omaha, NE
| | - David L Klinkebiel
- Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE
| | - Andrew M Donson
- Morgan Adams Pediatric Brain Tumor Research Program, University of Colorado School of Medicine, Denver, CO
| | - Deborah Perry
- Department of Pathology, Children's Hospital and Medical Center, Omaha, NE
| | - Michael Punsoni
- Department of Pathology, University of Nebraska Medical Center, Omaha, NE
| | - Geoffrey A Talmon
- Department of Pathology, University of Nebraska Medical Center, Omaha, NE
| | - Donald W Coulter
- Department of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE
| | - Daniel R Boue'
- Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital and the Ohio State University, Columbus, OH
| | - Matija Snuderl
- Department of Pathology, New York University Langone Health, New York, NY
| | - Mohd W Nasser
- Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE
| | - Surinder K Batra
- Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE
| | - Rajeev Vibhakar
- Morgan Adams Pediatric Brain Tumor Research Program, University of Colorado School of Medicine, Denver, CO
| | - Sidharth Mahapatra
- Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE.,Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE
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YWHAE silencing induces cell proliferation, invasion and migration through the up-regulation of CDC25B and MYC in gastric cancer cells: new insights about YWHAE role in the tumor development and metastasis process. Oncotarget 2018; 7:85393-85410. [PMID: 27863420 PMCID: PMC5356744 DOI: 10.18632/oncotarget.13381] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 10/27/2016] [Indexed: 12/16/2022] Open
Abstract
We previously observed reduced YWHAE (14-3-3ε) protein expression in a small set of gastric cancer samples. YWHAE may act as a negative regulator of the cyclin CDC25B, which is a transcriptional target of MYC oncogene. The understanding of YWHAE role and its targets is important for the better knowledge of gastric carcinogenesis. Thus, we aimed to evaluate the relationship among YWHAE, CDC25B, and MYC in vitro and in vivo. For this, we analyzed the YWHAE, CDC25B, and MYC expression in YWHA-silenced, CDC25B-silenced, and MYC-silenced gastric cancer cell lines, as well as in gastric cancer and non-neoplastic gastric samples. In gastric cancer cell lines, YWHAE was able to inhibit the cell proliferation, invasion and migration through the reduction of MYC and CDC25B expression. Conversely, MYC induced the cell proliferation, invasion and migration through the induction of CDC25B and the reduction of YWHAE. Most of the tumors presented reduced YWHAE and increased CDC25B expression, which seems to be important for tumor development. Increased MYC expression was a common finding in gastric cancer and has a role in poor prognosis. In the tumor initiation, the opposite role of YWHAE and CDC25B in gastric carcinogenesis seems to be independent of MYC expression. However, the inversely correlation between YWHAE and MYC expression seems to be important for gastric cancer cells invasion and migration. The interaction between YWHAE and MYC and the activation of the pathways related to this interaction play a role in the metastasis process.
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9
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MNT and Emerging Concepts of MNT-MYC Antagonism. Genes (Basel) 2017; 8:genes8020083. [PMID: 28230739 PMCID: PMC5333072 DOI: 10.3390/genes8020083] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 02/16/2017] [Indexed: 12/25/2022] Open
Abstract
MYC family proteins play fundamental roles in stem and progenitor cell homeostasis, morphogenesis and cancer. As expected for proteins that profoundly affect the fate of cells, the activities of MYC are regulated at a multitude of levels. One mechanism with the potential to broadly affect the activities of MYC is transcriptional antagonism by a group of MYC-related transcriptional repressors. From this group, the protein MNT has emerged as having perhaps the most far-reaching impact on MYC activities. In this review, we discuss the current understanding of MNT, its regulation and how, as a MYC antagonist, it functions both as a tumor suppressor and facilitator of MYC-driven proliferation and oncogenesis.
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10
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Leal MF, Wisnieski F, de Oliveira Gigek C, do Santos LC, Calcagno DQ, Burbano RR, Smith MC. What gastric cancer proteomic studies show about gastric carcinogenesis? Tumour Biol 2016; 37:9991-10010. [PMID: 27126070 DOI: 10.1007/s13277-016-5043-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 03/28/2016] [Indexed: 12/26/2022] Open
Abstract
Gastric cancer is a complex, heterogeneous, and multistep disease. Over the past decades, several studies have aimed to determine the molecular factors that lead to gastric cancer development and progression. After completing the human genome sequencing, proteomic technologies have presented rapid progress. Differently from the relative static state of genome, the cell proteome is dynamic and changes in pathologic conditions. Proteomic approaches have been used to determine proteome profiles and identify differentially expressed proteins between groups of samples, such as neoplastic and nonneoplastic samples or between samples of different cancer subtypes or stages. Therefore, proteomic technologies are a useful tool toward improving the knowledge of gastric cancer molecular pathogenesis and the understanding of tumor heterogeneity. This review aimed to summarize the proteins or protein families that are frequently identified by using high-throughput screening methods and which thus may have a key role in gastric carcinogenesis. The increased knowledge of gastric carcinogenesis will clearly help in the development of new anticancer treatments. Although the studies are still in their infancy, the reviewed proteins may be useful for gastric cancer diagnosis, prognosis, and patient management.
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Affiliation(s)
- Mariana Ferreira Leal
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, 04038-032, São Paulo, São Paulo, Brazil. .,Disciplina de Genética, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitão da Cunha - 1° andar, CEP 04023-900, São Paulo, Brazil.
| | - Fernanda Wisnieski
- Disciplina de Genética, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitão da Cunha - 1° andar, CEP 04023-900, São Paulo, Brazil
| | - Carolina de Oliveira Gigek
- Disciplina de Genética, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitão da Cunha - 1° andar, CEP 04023-900, São Paulo, Brazil
| | - Leonardo Caires do Santos
- Disciplina de Genética, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitão da Cunha - 1° andar, CEP 04023-900, São Paulo, Brazil
| | - Danielle Queiroz Calcagno
- Núcleo de Pesquisas em Oncologia, Hospital Universitário João de Barros Barreto, 66073-000, Belém, Pará, Brazil
| | - Rommel Rodriguez Burbano
- Laboratório de Citogenética Humana, Instituto de Ciências Biológicas, Universidade Federal do Pará, 66075-110, Belém, Pará, Brazil
| | - Marilia Cardoso Smith
- Disciplina de Genética, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitão da Cunha - 1° andar, CEP 04023-900, São Paulo, Brazil
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11
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Diolaiti D, McFerrin L, Carroll PA, Eisenman RN. Functional interactions among members of the MAX and MLX transcriptional network during oncogenesis. BIOCHIMICA ET BIOPHYSICA ACTA 2015; 1849:484-500. [PMID: 24857747 PMCID: PMC4241192 DOI: 10.1016/j.bbagrm.2014.05.016] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Revised: 04/23/2014] [Accepted: 05/14/2014] [Indexed: 01/27/2023]
Abstract
The transcription factor MYC and its related family members MYCN and MYCL have been implicated in the etiology of a wide spectrum of human cancers. Compared to other oncoproteins, such as RAS or SRC, MYC is unique because its protein coding region is rarely mutated. Instead, MYC's oncogenic properties are unleashed by regulatory mutations leading to unconstrained high levels of expression. Under both normal and pathological conditions MYC regulates multiple aspects of cellular physiology including proliferation, differentiation, apoptosis, growth and metabolism by controlling the expression of thousands of genes. How a single transcription factor exerts such broad effects remains a fascinating puzzle. Notably, MYC is part of a network of bHLHLZ proteins centered on the MYC heterodimeric partner MAX and its counterpart, the MAX-like protein MLX. This network includes MXD1-4, MNT, MGA, MONDOA and MONDOB proteins. With some exceptions, MXD proteins have been functionally linked to cell cycle arrest and differentiation, while MONDO proteins control cellular metabolism. Although the temporal expression patterns of many of these proteins can differ markedly they are frequently expressed simultaneously in the same cellular context, and potentially bind to the same, or similar DNA consensus sequence. Here we review the activities and interactions among these proteins and propose that the broad spectrum of phenotypes elicited by MYC deregulation is intimately connected to the functions and regulation of the other network members. Furthermore, we provide a meta-analysis of TCGA data suggesting that the coordinate regulation of the network is important in MYC driven tumorigenesis. This article is part of a Special Issue entitled: Myc proteins in cell biology and pathology.
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Affiliation(s)
- Daniel Diolaiti
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, USA
| | - Lisa McFerrin
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, USA
| | - Patrick A Carroll
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, USA
| | - Robert N Eisenman
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, USA.
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12
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Leal MF, Calcagno DQ, Demachki S, Assumpção PP, Chammas R, Burbano RR, Smith MDAC. Clinical implication of 14-3-3 epsilon expression in gastric cancer. World J Gastroenterol 2012; 18:1531-7. [PMID: 22509086 PMCID: PMC3319950 DOI: 10.3748/wjg.v18.i13.1531] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Revised: 12/23/2011] [Accepted: 12/31/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate for the first time the protein and mRNA expression of 14-3-3ε in gastric carcinogenesis.
METHODS: 14-3-3ε protein expression was determined by western blotting, and mRNA expression was examined by real-time quantitative RT-PCR in gastric tumors and their matched non-neoplastic gastric tissue samples.
RESULTS: Authors observed a significant reduction of 14-3-3ε protein expression in gastric cancer (GC) samples compared to their matched non-neoplastic tissue. Reduced levels of 14-3-3ε were also associated with diffuse-type GC and early-onset of this pathology. Our data suggest that reduced 14-3-3ε may have a role in gastric carcinogenesis process.
CONCLUSION: Our results reveal that the reduced 14-3-3ε expression in GC and investigation of 14-3-3ε interaction partners may help to elucidate the carcinogenesis process.
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13
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O'Meara E, Stack D, Lee CH, Garvin AJ, Morris T, Argani P, Han JS, Karlsson J, Gisselson D, Leuschner I, Gessler M, Graf N, Fletcher JA, O'Sullivan MJ. Characterization of the chromosomal translocation t(10;17)(q22;p13) in clear cell sarcoma of kidney. J Pathol 2012; 227:72-80. [DOI: 10.1002/path.3985] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Revised: 12/22/2011] [Accepted: 12/22/2011] [Indexed: 01/06/2023]
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14
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Wang H, Huang H, Li W, Jin X, Zeng J, Liu Y, Gu Y, Sun X, Wen G, Ding Y, Zhao L. Nuclear localization of 14-3-3epsilon inversely correlates with poor long-term survival of patients with colorectal cancer. J Surg Oncol 2011; 106:224-31. [PMID: 22105787 DOI: 10.1002/jso.22152] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Accepted: 10/31/2011] [Indexed: 01/21/2023]
Abstract
BACKGROUND 14-3-3ε regulates diverse biological processes and plays a significant role in the formation of malignant tumors. However, the localization and clinical significance of 14-3-3ε in colorectal cancer (CRC) have not been elucidated. METHODS We investigated 14-3-3ε expression and its prognostic significance in CRC. CRC surgical samples were taken from 137 clinicopathologically characterized CRC cases. 14-3-3ε expression was tested by immunohistochemical assay. Separate Western blot of nuclear and cytosol preparations confirmed nuclear localization of 14-3-3ε protein. RESULTS Nuclear expression of 14-3-3ε was observed in 76.9% of normal colorectal tissue and 78.8% of all CRC samples. Statistical analysis showed that there was significant difference of nuclear 14-3-3ε expression in patients categorized according to lymph node metastasis. A trend was identified between decreasing nuclear 14-3-3ε expression in CRC and worsening clinical prognosis. Multivariate analysis showed that loss of nuclear 14-3-3ε expression was an independent prognostic indicator for patient's survival. CONCLUSIONS The current data provide evidence that 14-3-3ε is not exclusively a cytosolic protein, but is also detectable within the nucleus. Our results suggest that nuclear 14-3-3ε as a suppressor may serve as important biomarker of tumor metastasis. Loss of nuclear 14-3-3ε is closely associated with poor overall survival in CRC patients.
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Affiliation(s)
- Hui Wang
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangzhou Medical College, Guangzhou, China
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15
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Abstract
Medulloblastoma is the most common infratentorial malignant tumour under 15 years of age. In recent protocols, the patients are stratified for treatment in standard risk or high risk, according to the clinical variables as age, localized or disseminated disease, degree of surgical resection and more recently expected biological behaviour based on retrospective and prospective studies of former samples analyzed. The objectives for future treatments are reduce morbidity without jeopardizing survival.
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16
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14-3-3epsilon contributes to tumour suppression in laryngeal carcinoma by affecting apoptosis and invasion. BMC Cancer 2010; 10:306. [PMID: 20565895 PMCID: PMC2904731 DOI: 10.1186/1471-2407-10-306] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2010] [Accepted: 06/19/2010] [Indexed: 12/22/2022] Open
Abstract
Background 14-3-3epsilon regulates a wide range of biological processes, including cell cycle control, proliferation, and apoptosis, and plays a significant role in neurogenesis and the formation of malignant tumours. However, the exact function and regulatory mechanism of 14-3-3epsilon in carcinogenesis have not been elucidated. Methods The expression of 14-3-3epsilon was assessed by RT-PCR and western blotting. The invasiveness and viability of Hep-2 cells were determined by the transwell migration assay and MTT assay, respectively. Cell cycle and apoptosis of Hep-2 cells were detected by flow cytometry. Results The mRNA and protein expression of 14-3-3epsilon in larynx squamous cell carcinoma (LSCC) tissues were significantly lower than those in clear surgical margin tissues. Statistical analysis showed that the 14-3-3epsilon protein level in metastatic lymph nodes was lower than that in paired tumour tissues. In addition, the protein level of 14-3-3epsilon in stage III or IV tumours was significantly lower than that in stage I or II tumours. Compared with control Hep-2 cells, the percentages of viable cells in the 14-3-3epsilon-GFP and negative control GFP groups were 36.68 ± 14.09% and 71.68 ± 12.10%, respectively. The proportions of S phase were 22.47 ± 3.36%, 28.17 ± 3.97% and 46.15 ± 6.82%, and the apoptotic sub-G1 populations were 1.23 ± 1.02%, 2.92 ± 1.59% and 13.72 ± 3.89% in the control, negative control GFP and 14-3-3epsilon-GFP groups, respectively. The percentages of the apoptotic cells were 0.84 ± 0.25%, 1.08 ± 0.24% and 2.93 ± 0.13% in the control, negative control GFP and 14-3-3epsilon-GFP groups, respectively. The numbers of cells that penetrated the filter membrane in the control, negative control GFP and 14-3-3epsilon-GFP groups were 20.65 ± 1.94, 17.63 ± 1.04 and 9.1 ± 0.24, respectively, indicating significant differences among the different groups. Conclusions Decreased expression of 14-3-3epsilon in LSCC tissues contributes to the initiation and progression of LSCC. 14-3-3epsilon can promote apoptosis and inhibit the invasiveness of LSCC.
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17
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Abstract
Myc is the most frequently deregulated oncogene in human tumors. The protein belongs to the Myc/Max/Mxd network of transcriptional regulators important for cell growth, proliferation, differentiation, and apoptosis. The ratio between Mnt/Max and c-Myc/Max on the 5'-CACGTG-3' E-box sequence at shared target genes is of great importance for cell cycle progression and arrest. Serum stimulation of quiescent cells results in phosphorylation of Mnt and disruption of the critical Mnt-mSin3-HDAC1 interaction. This in turn leads to increased expression of the Myc/Mnt target gene cyclin D2. It is therefore possible that Myc function relies on its ability to overcome transcriptional repression by Mnt and that relief of Mnt-mediated transcriptional repression is of greater importance for regulation of target genes than the sole activation by Myc. In addition, Mnt has many features of a tumor suppressor and may thus be nonfunctional or inactivated in human tumors. In summary, accumulating evidence supports the model of Mnt as the key regulator of the network in vivo.
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Affiliation(s)
- Therese Wahlström
- Department of Microbiology, Tumor, and Cell Biology (MTC), Karolinska Institutet, SE-171 77 Stockholm, Sweden
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18
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Hu L, Zhu YT, Qi C, Zhu YJ. Identification of Smyd4 as a potential tumor suppressor gene involved in breast cancer development. Cancer Res 2009; 69:4067-72. [PMID: 19383909 DOI: 10.1158/0008-5472.can-08-4097] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
To identify genes involved in breast tumorigenesis, we applied the retroviral LoxP-Cre system to a nontumorigenic mouse mammary epithelial cell line NOG8 to create random chromosome deletion/translocation. We found that the disruption of one allele of Smyd4 (SET and MYND domain containing 4) gene through chromosome translocation led to tumorigenesis. The expression of Smyd4 was markedly decreased in tumor cells. Re-expression of Smyd4 resulted in growth suppression of tumor cells and inhibition of tumor formation in nude mice. Furthermore, the RNA interference-mediated suppression of Smyd4 expression in human MCF10A mammary epithelial cells caused their growth in soft agar. Microarray studies revealed that platelet-derived growth factor receptor alpha polypeptide (Pdgfr-alpha) was highly expressed in tumor cells compared with NOG8 cells. Re-expression of Smyd4 significantly reduced the expression of Pdgfr-alpha in tumor cells. In human breast cancers, reverse transcription-PCR results revealed that Smyd4 expression was totally silenced in 2 of 10 specimens. These findings indicate that Smyd4, as a potential tumor suppressor, plays a critical role in breast carcinogenesis at least partly through inhibiting the expression of Pdgfr-alpha, and could be a novel target for improving treatment of breast cancer.
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Affiliation(s)
- Liping Hu
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611-3008, USA
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19
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Hutter G, Scheubner M, Ott G, Zimmermann Y, Hübler K, Roth S, Stilgenbauer S, Kalla J, Stöcklein H, Hiddemann W, Dreyling M. Allelic genotyping reveals a hierarchy of genomic alterations in mantle cell lymphoma associated to cell proliferation. Ann Hematol 2009; 88:821-8. [DOI: 10.1007/s00277-008-0686-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2008] [Accepted: 12/18/2008] [Indexed: 10/21/2022]
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20
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de Bont JM, Packer RJ, Michiels EM, den Boer ML, Pieters R. Biological background of pediatric medulloblastoma and ependymoma: a review from a translational research perspective. Neuro Oncol 2008; 10:1040-60. [PMID: 18676356 DOI: 10.1215/15228517-2008-059] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Survival rates of pediatric brain tumor patients have significantly improved over the years due to developments in diagnostic techniques, neurosurgery, chemotherapy, radiotherapy, and supportive care. However, brain tumors are still an important cause of cancer-related deaths in children. Prognosis is still highly dependent on clinical characteristics, such as the age of the patient, tumor type, stage, and localization, but increased knowledge about the genetic and biological features of these tumors is being obtained and might be useful to further improve outcome for these patients. It has become clear that the deregulation of signaling pathways essential in brain development, for example, sonic hedgehog (SHH), Wnt, and Notch pathways, plays an important role in pathogenesis and biological behavior, especially for medulloblastomas. More recently, data have become available about the cells of origin of brain tumors and the possible existence of brain tumor stem cells. Newly developed array-based techniques for studying gene expression, protein expression, copy number aberrations, and epigenetic events have led to the identification of other potentially important biological abnormalities in pediatric medulloblastomas and ependymomas.
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Affiliation(s)
- Judith M de Bont
- Department of Pediatric Oncology and Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
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21
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Genomic deletion and promoter methylation status of Hypermethylated in Cancer 1 (HIC1) in mantle cell lymphoma. J Hematop 2008; 1:85-95. [PMID: 19669207 PMCID: PMC2713485 DOI: 10.1007/s12308-008-0008-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2008] [Accepted: 05/10/2008] [Indexed: 10/26/2022] Open
Abstract
Mantle cell lymphomas (MCL), characterized by the t(11;14)(q13;q32), frequently carry secondary genetic alterations such as deletions in chromosome 17p involving the TP53 locus. Given that the association between TP53-deletions and concurrent mutations of the remaining allele is weak and based on our recent report that the Hypermethylated in Cancer 1 (HIC1) gene, that is located telomeric to the TP53 gene, may be targeted by deletions in 17p in diffuse large B-cell lymphoma (DLBCL), we investigated whether HIC1 inactivations might also occur in MCL. Monoallelic deletions of the TP53 locus were detected in 18 out of 59 MCL (31%), while overexpression of p53 protein occurred in only 8 out of 18 of these MCL (44%). In TP53-deleted MCL, the HIC1 gene locus was co-deleted in 11 out of 18 cases (61%). However, neither TP53 nor HIC1 deletions did affect survival of MCL patients. In most analyzed cases, no hypermethylation of the HIC1 exon 1A promoter was observed (17 out of 20, 85%). However, in MCL cell lines without HIC1-hypermethylation, the mRNA expression levels of HIC1 were nevertheless significantly reduced, when compared to reactive lymph node specimens, pointing to the occurrence of mechanisms other than epigenetic or genetic events for the inactivation of HIC1 in this entity.
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22
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Kaul R, Verma SC, Robertson ES. Protein complexes associated with the Kaposi's sarcoma-associated herpesvirus-encoded LANA. Virology 2007; 364:317-29. [PMID: 17434559 PMCID: PMC4067005 DOI: 10.1016/j.virol.2007.03.010] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2006] [Revised: 01/02/2007] [Accepted: 03/06/2007] [Indexed: 12/12/2022]
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the major biological cofactor contributing to development of Kaposi's sarcoma. KSHV establishes a latent infection in human B cells expressing the latency-associated nuclear antigen (LANA), a critical factor in the regulation of viral latency. LANA is known to modulate viral and cellular gene expression. We report here on some initial proteomic studies to identify cellular proteins associated with the amino and carboxy-terminal domains of LANA. The results of these studies show an association of known cellular proteins which support LANA functions and have identified additional LANA-associated proteins. These results provide new evidence for complexes involving LANA with a number of previously unreported functional classes of proteins including DNA polymerase, RNA helicase and cell cycle control proteins. The results also indicate that the amino terminus of LANA can interact with its carboxy-terminal domain. This interaction is potentially important for facilitating associations with other cell cycle regulatory proteins which include CENP-F identified in association with both the amino and carboxy-termini. These novel associations add to the diversity of LANA functions in relation to the maintenance of latency and subsequent transformation of KSHV infected cells.
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Affiliation(s)
| | | | - Erle S Robertson
- Address for Correspondence: 201E Johnson Pavilion, 3610 Hamilton Walk, Department of Microbiology and Tumor Virology Program of the Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 Phone: 215-746-0116 Fax: 215-898-9557 E-mail:
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23
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Funato Y, Miki H. Nucleoredoxin, a novel thioredoxin family member involved in cell growth and differentiation. Antioxid Redox Signal 2007; 9:1035-57. [PMID: 17567240 DOI: 10.1089/ars.2007.1550] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Thioredoxin (TRX) family proteins are involved in various biologic processes by regulating the response to oxidative stress. Nucleoredoxin (NRX), a relatively uncharacterized member of the TRX family protein, has recently been reported to regulate the Wnt/beta-catenin pathway, which itself regulates cell fate and early development, in a redox-dependent manner. In this review, we describe the TRX family proteins and discuss in detail the similarities and differences between NRX and other TRX family proteins. Although NRX possesses a conserved TRX domain and a catalytic motif for oxidoreductase activity, its sequence homology to TRX is not as high as that of the close relatives of TRX. The sequence of NRX is more similar to that of tryparedoxin (TryX), a TRX family member originally identified in parasite trypanosomes. We also discuss the reported properties and potential physiologic roles of NRX.
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Affiliation(s)
- Yosuke Funato
- Division of Cancer Genomics, Institute of Medical Science, University of Tokyo, Japan
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24
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Toyo-oka K, Bowen TJ, Hirotsune S, Li Z, Jain S, Ota S, Escoubet-Lozach L, Lozach LE, Garcia-Bassets I, Bassett IG, Lozach J, Rosenfeld MG, Glass CK, Eisenman R, Ren B, Hurlin P, Wynshaw-Boris A. Mnt-deficient mammary glands exhibit impaired involution and tumors with characteristics of myc overexpression. Cancer Res 2006; 66:5565-73. [PMID: 16740691 DOI: 10.1158/0008-5472.can-05-2683] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The proto-oncogene c-Myc plays a central role in cell growth and the development of human tumors. c-Myc interacts with Max and Myc-Max complexes bind to E-box and related sequences to activate transcription. Max also interacts with Mnt but Mnt-Max complexes repress transcription when bound to these sequences. MNT maps to human chromosome 17p13.3, a region frequently deleted in various human tumors, including mammary gland tumors. Consistent with the possibility that Mnt functions as a Myc antagonist, Mnt-deficient fibroblasts exhibit many of the hallmark characteristics of cells that overexpress Myc, and conditional (Cre/Lox) inactivation of Mnt in mammary gland epithelium leads to adenocarcinomas. Here, we further characterize mammary gland tissue following conditional deletion of Mnt in the mammary gland. We show that loss of Mnt severely disrupts mammary gland involution and leads to hyperplastic ducts associated with reduced numbers of apoptotic cells. These findings suggest that loss of Mnt in mammary tissue has similarities to Myc overexpression. We tested this directly by using promoter array analysis and mRNA expression analysis by oligonucleotide arrays. We found that Mnt and c-Myc bound to similar promoters in tumors from MMTV-c-Myc transgenic mice, and mRNA expression patterns were similar between mammary tumors from MMTV-Cre/Mnt(KO/CKO) and MMTV-c-Myc transgenic mice. These results reveal an important role for Mnt in pregnancy-associated mammary gland development and suggest that mammary gland tumorigenesis in the absence of Mnt is analogous to that caused by Myc deregulation.
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MESH Headings
- Animals
- Apoptosis/genetics
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/biosynthesis
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/deficiency
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism
- Female
- Gene Expression Regulation, Neoplastic
- Genes, Tumor Suppressor
- Lactation/physiology
- Mammary Glands, Animal/growth & development
- Mammary Glands, Animal/metabolism
- Mammary Glands, Animal/pathology
- Mammary Glands, Animal/physiology
- Mammary Neoplasms, Experimental/genetics
- Mammary Neoplasms, Experimental/metabolism
- Mammary Neoplasms, Experimental/pathology
- Mice
- Mice, Knockout
- Mice, Transgenic
- Promoter Regions, Genetic
- Protein Binding
- Proto-Oncogene Mas
- Proto-Oncogene Proteins c-myc/biosynthesis
- Proto-Oncogene Proteins c-myc/genetics
- Proto-Oncogene Proteins c-myc/metabolism
- Repressor Proteins/biosynthesis
- Repressor Proteins/genetics
- Repressor Proteins/metabolism
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Affiliation(s)
- Kazuhito Toyo-oka
- Department of Pediatrics, University of California, San Diego Comprehensive Cancer Center, La Jolla, California, USA
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25
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Popov N, Wahlström T, Hurlin PJ, Henriksson M. Mnt transcriptional repressor is functionally regulated during cell cycle progression. Oncogene 2005; 24:8326-37. [PMID: 16103876 DOI: 10.1038/sj.onc.1208961] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The Myc/Max/Mad network of transcription factors regulates cell proliferation, differentiation, and transformation. Similar to other proteins of the network, Mnt forms heterodimers with Max and binds CACGTG E-Box elements. Transcriptional repression by Mnt is mediated through association with mSin3, and deletion of the mSin3-interacting domain (SID) converts Mnt to a transcriptional activator. Mnt is coexpressed with Myc in proliferating cells and has been suggested to be a modulator of Myc function. We report that Mnt is expressed both in growth-arrested and proliferating mouse fibroblasts and is phosphorylated when resting cells are induced to re-enter the cell cycle. Importantly, the interaction between Mnt and mSin3 is disrupted upon serum stimulation resulting in decreased Mnt-associated HDAC activity. Furthermore, we demonstrate that Mnt binds and recruits mSin3 to the Myc target gene cyclin D2 in quiescent mouse fibroblasts. Interference with Mnt expression by RNAi resulted in upregulation of cyclin D2 expression in growth-arrested fibroblasts, supporting the view that Mnt represses cyclin D2 transcription in quiescent cells. Our data suggest a model in which phosphorylation of Mnt at cell cycle entry results in disruption of Mnt-mSin3-HDAC1 interaction, which allows induction of Myc target genes by release of Mnt-mediated transcriptional repression.
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Affiliation(s)
- Nikita Popov
- Microbiology and Tumor Biology Center, Karolinska Institutet, Box 280, SE-171 77 Stockholm, Sweden
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26
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Navajas Gutiérrez A, Fernández-Teijeiro Alvarez A. Embryonic tumours of the central nervous system. Clin Transl Oncol 2005; 7:219-27. [PMID: 15960935 DOI: 10.1007/bf02712821] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Aurora Navajas Gutiérrez
- Unidad de Oncología Pediátrica, Hospital de Cruces-Vizcaya, University of the Basque Country, 48903 Baracaldo, Vizcaya, Spain.
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