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Al-Hawary SIS, Pallathadka H, Hjazi A, Zhumanov ZE, Alazbjee AAA, Imad S, Alsalamy A, Hussien BM, Jaafer NS, Mahmoudi R. ETS transcription factor ELK3 in human cancers: An emerging therapeutic target. Pathol Res Pract 2023; 248:154728. [PMID: 37542863 DOI: 10.1016/j.prp.2023.154728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 07/26/2023] [Accepted: 07/29/2023] [Indexed: 08/07/2023]
Abstract
Cancer is a genetic and complex disorder, resulting from several events associated with onset, development, and metastasis. Tumor suppressors and oncogenes are among the main regulators of tumor progression, contributing to various cancer-related behaviors like cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), cell cycle, and apoptosis. Transcription factors (TFs) could act as tumor suppressors or oncogenes in cancer progression. E-twenty-six/E26 (ETS) family of TFs have a winged helix-turn-helix (HLH) motif, which interacted with specific DNA regions with high levels of purines and GGA core. ETS proteins act as transcriptional repressors or activators to modulate the expression of target genes. ETS transcription factor ELK3 (ELK3), as a type of ETS protein, was shown to enhance in various cancers, suggesting that it may have an oncogenic role. These studies indicated that ELK3 promoted invasion, migration, cell cycle, proliferation, and EMT, and suppressed cell apoptosis. In addition, these studies demonstrated that ELK3 could be a promising diagnostic and prognostic biomarker in human cancer. Moreover, accumulating data proved that ELK3 could be a novel chemoresistance mediator in human cancer. Here, we aimed to explore the overall change of ELK3 and its underlying molecular mechanism in human cancers. Moreover, we aimed to investigate the potential role of ELK3 as a prognostic and diagnostic biomarker as well as its capability as a chemoresistance mediator in cancer.
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Affiliation(s)
| | | | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Ziyadulla Eshmamatovich Zhumanov
- Department of Pathological Anatomy, With a Section-biopsy Course, Samarkand State Medical Institute, Amir Temur Street 18, Samarkand, Uzbekistan; Department of Scientific Affairs, Tashkent State Dental Institute, Makhtumkuli Street 103, Tashkent 100047, Uzbekistan
| | | | - Shad Imad
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Ali Alsalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| | - Beneen M Hussien
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Noor Sadiq Jaafer
- Department of Medical Laboratory Technologies, Al Rafidain University College, Bagdad, Iraq
| | - Reza Mahmoudi
- Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
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Heo SH, Cho JY. ELK3 suppresses angiogenesis by inhibiting the transcriptional activity of ETS-1 on MT1-MMP. Int J Biol Sci 2014; 10:438-47. [PMID: 24719561 PMCID: PMC3979996 DOI: 10.7150/ijbs.8095] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2013] [Accepted: 03/07/2014] [Indexed: 11/05/2022] Open
Abstract
Ets transcription factors play important roles in vasculogenesis and angiogenesis. Knockout of the Ets gene family members in mice resulted in disrupted angiogenesis and malformed vascular systems. In this study, the role and mechanism of ELK3, an Ets factor, in angiogenesis was investigated using ELK3-specific siRNA in human vascular endothelial cells (HUVECs) and in vivo implantation assay. The suppression of ELK3 expression resulted in the reinforcement of VEGF-induced tube formation in HUVECs. The in vivo Matrigel plug assay also showed that ELK3 knockdown resulted in increased angiogenesis. Luciferase activity of the MT1-MMP promoter induced by ETS-1 factor was attenuated ELK3 co-transfection. CHIP assay showed the binding of ELK3 on the MT1-MMP promoter. MT1-MMP knockdown in the ELK3 knockdowned cells resulted in the decrease of tube formation suggesting that MT1-MMP transcriptional repression is required for ELK3-mediated anti-angiogenesis effect. Our data also showed that the suppressive effect of ELK3 on the angiogenesis was partly due to the inhibitory effect of ELK3 to the ETS-1 transcriptional activity on the MT1-MMP promoter rather than direct suppression of ELK3 on the target gene, since the expression level of co-repressor Sin3A is low in endothelial cells. Our results suggest that ELK3 plays a negative role of VEGF-induced angiogenesis through indirectly inhibiting ETS-1 function.
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Affiliation(s)
- Sun-Hee Heo
- Department of Veterinary Biochemistry, BK21 Plus, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Je-Yoel Cho
- Department of Veterinary Biochemistry, BK21 Plus, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
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Besnard A, Galan-Rodriguez B, Vanhoutte P, Caboche J. Elk-1 a transcription factor with multiple facets in the brain. Front Neurosci 2011; 5:35. [PMID: 21441990 PMCID: PMC3060702 DOI: 10.3389/fnins.2011.00035] [Citation(s) in RCA: 139] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2010] [Accepted: 03/04/2011] [Indexed: 12/30/2022] Open
Abstract
The ternary complex factor (TCF) Elk-1 is a transcription factor that regulates immediate early gene (IEG) expression via the serum response element (SRE) DNA consensus site. Elk-1 is associated with a dimer of serum response factor (SRF) at the SRE site, and its phosphorylation occurs at specific residues in response to mitogen-activated protein kinases (MAPKs), including c-Jun-N terminal kinase (JNK), p38/MAPK, and extracellular-signal regulated kinase (ERK). This phosphorylation event is critical for triggering SRE-dependent transcription. Although MAPKs are fundamental actors for the instatement and maintenance of memory, and much investigation of their downstream signaling partners have been conducted, no data yet clearly implicate Elk-1 in these processes. This is partly due to the complexity of Elk-1 sub-cellular localization, and hence functions, within neurons. Elk-1 is present in its resting state in the cytoplasm, where it colocalizes with mitochondrial proteins or microtubules. In this particular sub-cellular compartment, overexpression of Elk-1 is toxic for neuronal cells. When phosphorylated by the MAPK/ERK, Elk-1 translocates to the nucleus where it is implicated in regulating chromatin remodeling, SRE-dependent transcription, and neuronal differentiation. Another post-translational modification is the conjugation to SUMO (Small Ubiquitin-like MOdifier), which relocalizes Elk-1 in the cytoplasm. Thus, Elk-1 plays a dual role in neuronal functions: pro-apoptotic within the cytoplasm, and pro-differentiation within the nucleus. To address the role of Elk-1 in the brain, one must be aware of its multiple facets, and design molecular tools that will shut down Elk-1 expression, trafficking, or activation, in specific neuronal compartments. We summarize in this review the known molecular functions of Elk-1, its regulation in neuronal cells, and present evidence of its possible implication in model systems of synaptic plasticity, learning, but also in neurodegenerative diseases.
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Affiliation(s)
- Antoine Besnard
- Laboratoire de Physiopathologie des Maladies du Système Nerveux Central, UMR CNRS-7224 CNRS et UMRS-INSERM 952, Université Pierre et Marie Curie-Paris 6 Paris, France
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4
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Zhang HQ, Haga S, Fukai M, Oikawa Y, Inoue H, Ogawa W, Kano A, Maruyama A, Fu XY, Todo S, Enosawa S, Ozaki M. Identification of de novo STAT3 target gene in liver regeneration. Hepatol Res 2008; 38:374-84. [PMID: 18021230 DOI: 10.1111/j.1872-034x.2007.00278.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
UNLABELLED The process of liver regeneration is regulated by complex mechanisms. Although signal transducer and activator of transcription-3 (STAT3), a transcription factor which targets mainly mitotic genes, definitely plays an important role in liver regeneration, the exact roles of STAT3 are not completely understood. AIM In this report, we tried to search for a new target of STAT3 involved in liver regeneration in mice. METHODS We generated liver-specific STAT3 knockout (L-S3KO) mice and a STAT3 knockout cell line of mouse origin. Using chromatin immunoprecipitation, we screened 12 genes to which STAT3 binds after partial hepatectomy (PH). Of these genes, we analyzed the S3-IE3 clone that is located on chromosome-3 and possesses STAT3 binding sites in it. RESULTS We showed that STAT3 binds to a specific site on S3-IE3, and that interleukin-6 (IL-6) stimulates its transcriptional activity. The mRNA and protein levels of the net gene, which is located downstream of S3-IE3, were negatively regulated in the control cells, but not in the STAT3 knockout cells after IL-6 stimulation. Similarly in in vivo mouse PH, the mRNA and protein levels of net were also negatively regulated after PH, but not in L-S3KO mice. CONCLUSION The net gene is located downstream of a newly-recognized STAT3 binding site (S3-IE3) and negatively regulated after IL-6 stimulation and PH, although its role is still unclear.
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Affiliation(s)
- Hui-Qi Zhang
- Department of Innovative Surgery, National Research Institute for Child Health and Development, Tokyo, and Japan Association for the Advancement of Medical Equipment, Tokyo, Japan
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Chen AG, Yu ZC, Yu XF, Cao WF, Ding F, Liu ZH. Overexpression of Ets-like protein 1 in human esophageal squamous cell carcinoma. World J Gastroenterol 2006; 12:7859-63. [PMID: 17203534 PMCID: PMC4087556 DOI: 10.3748/wjg.v12.i48.7859] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the expression pattern of Ets-like protein 1 (Elk-1) in human esophageal squamous cell carcinoma (ESCC) and to analyze its relationship with clinicopathologic parameters.
METHODS: The expression of Elk-1 in fresh esophageal cancer tissues and their corresponding normal mucosae was detected immunohistochemically (IHC) by means of tissue microarray (TMA). Its correlation with clinical characteristics was evaluated and analyzed by univariate analysis. All statistical analyses were performed by SPSS version 13.0.
RESULTS: Expression level of transcription factor Elk-1 increased in 78.5% (84/107) ESCC tissues compared with their matched normal esophageal epithelium. However, the expression of Elk-1 did not show any obvious correlation with degree of differentiation of esophageal carcinoma (in well-differentiated, moderately-differentiated and poorly-differentiated tumors, the increased expression was 7/8, 60/74, and 19/25, respectively, P > 0.05). Moreover, no obvious correlation was found with lymph node metastasis and depth of invasion.
CONCLUSION: Increased expression of transcription factor Elk-1 may play an important role in esophageal carcinogenesis.
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Affiliation(s)
- An-Guo Chen
- Department of Thoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
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Zimonjic DB, Kato Y, Ying H, Popescu NC, Cheng SY. Chromosomal aberrations in cell lines derived from thyroid tumors spontaneously developed in TRbetaPV/PV mice. ACTA ACUST UNITED AC 2005; 161:104-9. [PMID: 16102579 DOI: 10.1016/j.cancergencyto.2005.02.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2004] [Accepted: 02/03/2005] [Indexed: 11/27/2022]
Abstract
The etiology and genetic alterations of follicular thyroid carcinoma are not well understood. By targeting a mutation (PV) into the thyroid hormone receptor beta gene (TRbetaPV mouse), we created a knock-in mutant TRbeta(PV/PV) mouse that spontaneously develop follicular thyroid carcinoma with progression to metastasis similar to human follicular thyroid carcinoma. This mouse model provides a valuable tool to ascertain the nature and the extent of genomic rearrangements that occur during carcinogenesis of the thyroid. Spectral karyotyping analysis (SKY) of seven cell lines derived from thyroid tumors developed in TRbeta(PV/PV) mice showed that all of them had abnormal karyotypes, with chromosome number ranging from near-diploid (39-42 chromosomes) to hypotetraploid (63-79 chromosomes). These seven cell lines also exhibited a variety of structural chromosomal aberrations, including common recurrent translocations and deletions. This SKY analysis shows that the development and progression of follicular thyroid carcinoma in knock-in TRbeta(PV/PV) mutant mice comprise recurrent structural and numerical genomic changes, some of which mimic those described in human thyroid cancer.
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Affiliation(s)
- Drazen B Zimonjic
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, 37 Convent Drive MSC 4262, Building 37/Room 4128C, Bethesda, MD 20892-4262, USA.
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7
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Abstract
The three ternary complex factors (TCFs) Elk-1, Net and Sap-1 form a subfamily of the E twenty-six (Ets) domain transcription factors. Their characteristic property is the ability to form a ternary nucleoprotein complex with the serum response factor (SRF) over the serum response element (SRE) of the c-fos promoter. The molecular mechanisms that underlie the function and regulation of these factors have been extensively studied and the TCFs are a paradigm for the study of transcriptional regulation in response to extracellular signalling through the mitogen-activated protein (MAP) kinase pathway. As final effectors of multiple signalling pathways and components of protein complexes on immediate early promoters, they represent key elements in the complex and dynamic regulation of gene expression. This review summarises the molecular, structural and biochemical studies that have led to the understanding of the functional domains of the TCFs, ternary complex formation, transcriptional regulation, protein partners and target genes in cell lines. Finally, the emerging studies of the biological roles of the TCFs in vivo will be discussed.
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Affiliation(s)
- Gilles Buchwalter
- Institut de Génétique et Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, BP 101142, CNRS, INSERM, ULP, 67404 Illkirch Cedex, France
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Cesari F, Brecht S, Vintersten K, Vuong LG, Hofmann M, Klingel K, Schnorr JJ, Arsenian S, Schild H, Herdegen T, Wiebel FF, Nordheim A. Mice deficient for the ets transcription factor elk-1 show normal immune responses and mildly impaired neuronal gene activation. Mol Cell Biol 2004; 24:294-305. [PMID: 14673163 PMCID: PMC303347 DOI: 10.1128/mcb.24.1.294-305.2004] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The transcription factor Elk-1 belongs to the ternary complex factor (TCF) subfamily of Ets proteins. TCFs interact with serum response factor to bind jointly to serum response elements in the promoters of immediate-early genes (IEGs). TCFs mediate the rapid transcriptional response of IEGs to various extracellular stimuli which activate mitogen-activated protein kinase signaling. To investigate physiological functions of Elk-1 in vivo, we generated Elk-1-deficient mice by homologous recombination in embryonic stem cells. These animals were found to be phenotypically indistinguishable from their wild-type littermates. Histological analysis of various tissues failed to reveal any differences between Elk-1 mutant and wild-type mice. Elk-1 deficiency caused no changes in the proteomic displays of brain or spleen extracts. Also, no immunological defects could be detected in mice lacking Elk-1, even upon infection with coxsackievirus B3. In mouse embryonic fibroblasts, Elk-1 was dispensable for c-fos and Egr-1 transcriptional activation upon stimulation with serum, lysophosphatidic acid, or tetradecanoyl phorbol acetate. However, in brains of Elk-1-deficient mice, cortical and hippocampal CA1 expression of c-fos, but not Egr-1 or c-Jun, was markedly reduced 4 h following kainate-induced seizures. This was not accompanied by altered patterns of neuronal apoptosis. Collectively, our data indicate that Elk-1 is essential neither for mouse development nor for adult life, suggesting compensatory activities by other TCFs.
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Affiliation(s)
- Francesca Cesari
- Abteilung Molekularbiologie, Universitätsklinikum Tübingen, Tübingen, Germany
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Liao DJ, Du QQ, Yu BW, Grignon D, Sarkar FH. Novel perspective: focusing on the X chromosome in reproductive cancers. Cancer Invest 2003; 21:641-58. [PMID: 14533452 DOI: 10.1081/cnv-120022385] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
In an XX female, one of the two X chromosomes has been inactivated during early embryonic life to achieve a compensation of X-linked gene products between males and females, leaving only one allele of X-linked genes functional. There are some X-linked genes escaping the X-inactivation, i.e., being expressed from both alleles. Escape from X-inactivation varies at different levels; some genes have both alleles active in some women but only one allele active in others, whereas some other genes have both alleles active in neoplastic tissue but only one allele active normally. The X-inactivation may be considered functionally equivalent to a loss of heterozygosity (LOH) for some genes, whereas escape from X-inactivation may be equivalent to functional gene amplification for others. The physiological LOH may make X-linked tumor suppressor genes lose their function more easily, compared with autosomal tumor suppressor genes, thus predisposing women to cancer formation more easily. Moreover, the human X chromosome contains many genes related to cancer or to sex and reproduction. All these properties of the X chromosome suggest that it may play more important roles than any autosomal chromosome in the development and progression of reproductive and urologic cancers.
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Affiliation(s)
- Dezhong Joshua Liao
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.
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Shaw PE, Saxton J. Ternary complex factors: prime nuclear targets for mitogen-activated protein kinases. Int J Biochem Cell Biol 2003; 35:1210-26. [PMID: 12757758 DOI: 10.1016/s1357-2725(03)00031-1] [Citation(s) in RCA: 106] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Ternary complex factors (TCFs), a subgroup of the ETS protein family, were first described in the context of c-fos gene regulation. Subsequently, their early identification as nuclear targets for mitogen-activated protein kinases served to exemplify the fundamental links in eukaryotic cells between growth factor-mediated signalling pathways and gene control. This article provides an overview of recent work on ternary complex factors, addressing their expression and molecular structure, as well as how selective interactions with members of other protein families serve to up-1 regulate or restrict their activity. Although only one genetic study on ternary complex factors has been published to date, unravelling of the underlying molecular events provides a basis for tentative predictions about their biological roles in mammalian organisms.
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Affiliation(s)
- Peter E Shaw
- Queen's Medical Centre, School of Biomedical Sciences, University of Nottingham, UK.
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Riemenschneider MJ, Knobbe CB, Reifenberger G. Refined mapping of 1q32 amplicons in malignant gliomas confirms MDM4 as the main amplification target. Int J Cancer 2003; 104:752-7. [PMID: 12640683 DOI: 10.1002/ijc.11023] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
We previously reported on the amplification and overexpression of the mouse double minute 4 homolog gene (MDM4) from 1q32 in a subset of malignant gliomas (Riemenschneider et al., Cancer Res 1999;59:6091-6). More recently, amplification and overexpression of the neighboring contactin 2 gene (CNTN2) was reported in individual malignant gliomas without MDM4 amplification (Rickman et al., Cancer Res 2001;61:2162-8). To address the question of whether 1q32 carries 2 independent amplification targets or a common target other than MDM4 and CNTN2, we analyzed primary malignant gliomas for amplification and overexpression of 17 different genes from this region. Our results indicate a single region of amplification that comprises the genes MDM4, GAC1, PIK3C2B and PEPP3, with only MDM4 amplification being invariably associated with overexpression. CNTN2 was found to be coamplified with MDM4 in 3 malignant gliomas but overexpressed in only 1 of these tumors. No CNTN2 amplification was detected in any of 102 malignant gliomas without MDM4 amplification. Our data therefore corroborate the notion that MDM4 is the main amplification target on 1q32 in malignant gliomas. However, coamplification and overexpression of adjacent genes may provide an additional growth advantage in some malignant gliomas with MDM4 amplification.
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Carinci F, Volinia S, Rubini C, Fioroni M, Francioso F, Arcelli D, Pezzetti F, Piattelli A. Genetic profile of clear cell odontogenic carcinoma. J Craniofac Surg 2003; 14:356-62. [PMID: 12826807 DOI: 10.1097/00001665-200305000-00014] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
In the head and neck region, clear cell tumors are usually derived from salivary glands, odontogenic tissues, and metastasis. The World Health Organization has classified clear cell odontogenic tumor among benign tumors, but it is now recognized as a more sinister lesion, and current opinion is that it should be designated as a carcinoma. It is characterized by aggressive growth, recurrences, and metastasis. By using complementary DNA microarrays, several genes in clear cell odontogenic tumor were identified that are differentially regulated when compared with non-tumor tissue. In conclusion, the first genetic profiling of clear odontogenic carcinoma is reported. DNA microarrays can potentially help in identifying some genes whose products could be disease-specific targets for cancer therapy as well as a tool for better classifying odontogenic tumor.
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Affiliation(s)
- Francesco Carinci
- Departments of Maxillofacial Surgery, University of Ferrara, Arcispedale S. Anna, Corso Giovecca 203, 44100 Ferrara, Italy.
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Murty VV, Montgomery K, Dutta S, Bala S, Renault B, Bosl GJ, Kucherlapati R, Chaganti RS. A 3-Mb high-resolution BAC/PAC contig of 12q22 encompassing the 830-kb consensus minimal deletion in male germ cell tumors. Genome Res 1999. [PMID: 10413405 DOI: 10.1101/gr.9.7.662] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Cytogenetic and molecular genetic analyses have shown that the 12q22 region is recurrently deleted in male germ cell tumors (GCTs), suggesting that this site may harbor a tumor suppressor gene (TSG). Previous loss of heterozygosity (LOH) analyses identified a consensus minimal deleted region between the markers D12S377 and D12S296, and a YAC clone contig covering the region was generated. Here, we describe a high-resolution sequence-ready physical map of this contig covering a 3-Mb region. The map comprised of 52 cosmids, 49 PACs, and 168 BACs that were anchored to the previous YAC contig; 99 polymorphic, nonpolymorphic, EST, and gene-based markers are now placed on this map in a unique order. Of these, 61 markers were isolated in the present study, including one that was polymorphic. In addition, we have narrowed the minimal deletion to approximately 830 kb between D12S1716 (proximal) and P382A8-AG (distal) by LOH analysis of 108 normal-tumor DNAs from GCT patients using 21 polymorphic STSs. These physical and deletion maps should prove useful for identification of the candidate TSG in GCTs, provide framework to generate complete DNA sequence, and ultimately generate a gene map of this segment of the chromosome 12. [The sequence data described in this paper have been submitted to the Genome Survey Sequence under accession nos. AQ254896-AQ254955 and AQ269251-AQ269266. Online supplementary material is available at http://www.genome.org]
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Affiliation(s)
- V V Murty
- Department of Pathology, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA.
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14
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Zimonjic DB, Keck CL, Thorgeirsson SS, Popescu NC. Novel recurrent genetic imbalances in human hepatocellular carcinoma cell lines identified by comparative genomic hybridization. Hepatology 1999; 29:1208-14. [PMID: 10094966 DOI: 10.1002/hep.510290410] [Citation(s) in RCA: 100] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
To search for recurrent and specific genomic alterations in human hepatocellular carcinoma (HCC), we examined 18 cell lines by comparative genomic hybridization (CGH), a molecular cytogenetic approach that allows positional identification of gains and losses of DNA sequences of the entire tumor genome. We report here a distinct pattern of multiple recurrent DNA copy-number gains and losses that include alterations frequently seen in other neoplasias as well as changes potentially specific for HCC. The most frequent gains were localized on 1p34.3-35, 1p33-34.1, 1q21-23, 1q31-32, 6p11-12, 7p21, 7q11.2, 8q24.1-24.2, 11q11-13, 12q11-13, 12q23, 17q11. 2-21, 17q23-24, and 20p11.1-q13.2. Recurrent losses were mapped on 3p12-14, 3q25, 4p12-14, 4q13-34, 5q21, 6q25-26, 8p11.2-23, 9p12-24, 11q23-24, 13q12-33, 14q12-13, 15q25-26, 18q11.2-22.2, and 21q21-22. Seventeen genomic imbalances are novel in HCC, thus extending significantly the map of genetic changes and providing a starting point for the isolation of new genes relevant in pathogenesis of liver neoplasia, as well as providing molecular probes for both diagnosis and monitoring treatment of the disease.
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Affiliation(s)
- D B Zimonjic
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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15
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Harindranath N, Mills FC, Mitchell M, Meindl A, Max EE. The human elk-1 gene family: the functional gene and two processed pseudogenes embedded in the IgH locus. Gene X 1998; 221:215-24. [PMID: 9795224 DOI: 10.1016/s0378-1119(98)00448-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
Elk-1 is a transcription factor whose activation by several mitogen-activated protein kinases (MAPKs) mediates the immediate early responses of the c-fos promoter to growth factors and other stimuli. Here, we report the structure of the human elk-1 gene, which we have localized about 6.5kb upstream of the properdin gene on the X chromosome. The coding sequence is interrupted by four introns; two additional introns lie within the 5' untranslated region. We have also found two elk-1-related processed pseudogenes in the human immunoglobulin heavy chain (IgH) locus, accounting for 'elk-2' previously visualized by in-situ hybridization at 14q32. A processed pseudogene evidently inserted downstream of a primordial immunoglobulin Calpha gene and was duplicated along with part of the IgH locus. Gene/pseudogene sequence comparisons and Southern blots of primate DNAs suggest that both the pseudogene insertion and the locus duplication occurred between about 30 and 60 million years ago.
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Affiliation(s)
- N Harindranath
- Center for Biologics, Evaluation and Research, FDA, 8800 Rockville Pike, Bethesda, MD 20892, USA
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Aryee DN, Petermann R, Kos K, Henn T, Haas OA, Kovar H. Cloning of a novel human ELF-1-related ETS transcription factor, ELFR, its characterization and chromosomal assignment relative to ELF-1. Gene 1998; 210:71-8. [PMID: 9524226 DOI: 10.1016/s0378-1119(98)00022-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The ETS gene family encodes a group of proteins that function as transcription factors under physiological conditions and, if aberrantly expressed, can lead to cellular transformation. ETS transcription factors are characterized by a unique conserved DNA binding domain. A subset of these proteins is rearranged with EWS in Ewing tumors (ET). We recently described a spectrum of ETS genes coexpressed with EWS-FLI1 in an ETcell line to define proteins that potentially compete in target site selection. We now report on the cloning and characterization of a novel ETS family member, ELFR, displaying 92% homology to ELF-1 in its DNA binding domain while diverging in the rest of the protein. ELFR expression was found in a very tissue restricted pattern with the highest abundancy in placenta. We also report the chromosomal assignment of ELFR and ELF-1 to Xq26 and 13q13, respectively, by means of fluorescence in-situ hybridization (FISH).
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MESH Headings
- Amino Acid Sequence
- Chromosome Mapping
- Chromosomes, Human, Pair 13/genetics
- Cloning, Molecular
- DNA-Binding Proteins/chemistry
- DNA-Binding Proteins/genetics
- Gene Expression Regulation, Neoplastic/genetics
- Genes, Neoplasm/genetics
- Genes, Reporter/genetics
- Humans
- In Situ Hybridization, Fluorescence
- Molecular Sequence Data
- RNA, Messenger/metabolism
- Sarcoma, Ewing/chemistry
- Sequence Alignment
- Sequence Analysis, DNA
- Transcription Factors/chemistry
- Transcription Factors/genetics
- Tumor Cells, Cultured
- X Chromosome/genetics
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Affiliation(s)
- D N Aryee
- Children's Cancer Research Institute (CCRI), St. Anna Kinderspital, Kinderspitalgasse 6, A-1090, Vienna, Austria
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Giovane A, Sobieszczuk P, Ayadi A, Maira SM, Wasylyk B. Net-b, a Ras-insensitive factor that forms ternary complexes with serum response factor on the serum response element of the fos promoter. Mol Cell Biol 1997; 17:5667-78. [PMID: 9315625 PMCID: PMC232415 DOI: 10.1128/mcb.17.10.5667] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The Ras signalling pathway targets transcription factors such as the ternary complex factors that are recruited by the serum response factor to form complexes on the serum response element (SRE) of the fos promoter. We have identified a new ternary complex factor, Net-b. We report the features of the net gene and show that it produces several splice variants, net-b and net-c. net-b RNA and protein are expressed in a variety of tissues and cell lines. net-c RNA is expressed at low levels, and the protein was not detected, raising the possibility that it is a cryptic splice variant. We have studied the composition of ternary complexes that form on the SRE of the fos promoter with extracts from fibroblasts (NIH 3T3) cultured under various conditions and pre-B cells (70Z/3) before and after differentiation with lipopolysaccharide (LPS). The fibroblast complexes contain mainly Net-b followed by Sap1 and Elk1. Net-b complexes, as well as Sap1 and Elk1, are induced by epidermal growth factor (EGF) stimulation of cells cultured in low serum. Pre-B-cell complexes contain mainly Sap1, with less of Net-b and little of Elk1. There is little change upon LPS-induced differentiation compared to the increase with EGF in fibroblasts. We have also found that Net-b is a nuclear protein that constitutively represses transcription. Net-b is not activated by Ras signalling, in contrast to Net, Sap1a, and Elk1. We have previously reported that down-regulation of Net proteins with antisense RNA increases SRE activity. The increase in SRE activity is observed at low serum levels and is even greater after serum stimulation, showing that the SRE is under negative regulation by Net proteins and the level of repression increases during induction. Net-b, the predominant factor in ternary complexes in fibroblasts, may both keep the activity of the SRE low in the absence of strong inducing conditions and rapidly shut the activity off after stimulation.
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Affiliation(s)
- A Giovane
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, ULP, Illkirch, France
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