Oncogenes and tumor angiogenesis: The HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner
Like other types of pre-malignant lesions and carcinoma, angiogenesis is associated with high-grade cervical dysplasia and with invasive squamous carcinoma of the cervix. Vascular endothelial cell growth factor (VEGF) is known to be one of the most important inducers of angiogenesis and is upregulat...
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| Veröffentlicht in: | Oncogene 2000-09, Vol.19 (40), p.4611-4620 |
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| description | Like other types of pre-malignant lesions and carcinoma, angiogenesis is associated with high-grade cervical dysplasia and with invasive squamous carcinoma of the cervix. Vascular endothelial cell growth factor (VEGF) is known to be one of the most important inducers of angiogenesis and is upregulated in carcinoma of the cervix. Human Papilloma Virus 16 (HPV-16) has been etiologically linked to human cervical cancer, and the major oncogenic proteins encoded by the viral genome, E6 and E7, are involved in the immortalization of target cells. Because several oncogenes including mutant ras, EGF receptor, ErbB2/Her2, c-myc and v-src upregulate VEGF expression, we asked whether HVP-16 E6 oncoprotein could act in a similar fashion. We found that HPV-16 E6-positive cells generally express high levels of VEGF message. Furthermore, co-expression of the VEGF promoter-Luc (luciferase) reporter gene with E6 in both human keratinocytes and mouse fibroblast showed that E6 oncoprotein upregulates VEGF promoter activity, and does so in a p53 independent manner. An E6 responsive region which comprises four Sp-1 sites, between -194 and -50 bp of the VEGF promoter, is also necessary for constitutive VEGF transcription. Taken together, our results suggest the possibility that the HPV oncoprotein E6 may contribute to tumor angiogenesis by direct stimulation of the VEGF gene. |
| doi_str_mv | 10.1038/sj.onc.1203817 |
| format | Article |
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Vascular endothelial cell growth factor (VEGF) is known to be one of the most important inducers of angiogenesis and is upregulated in carcinoma of the cervix. Human Papilloma Virus 16 (HPV-16) has been etiologically linked to human cervical cancer, and the major oncogenic proteins encoded by the viral genome, E6 and E7, are involved in the immortalization of target cells. Because several oncogenes including mutant ras, EGF receptor, ErbB2/Her2, c-myc and v-src upregulate VEGF expression, we asked whether HVP-16 E6 oncoprotein could act in a similar fashion. We found that HPV-16 E6-positive cells generally express high levels of VEGF message. Furthermore, co-expression of the VEGF promoter-Luc (luciferase) reporter gene with E6 in both human keratinocytes and mouse fibroblast showed that E6 oncoprotein upregulates VEGF promoter activity, and does so in a p53 independent manner. An E6 responsive region which comprises four Sp-1 sites, between -194 and -50 bp of the VEGF promoter, is also necessary for constitutive VEGF transcription. Taken together, our results suggest the possibility that the HPV oncoprotein E6 may contribute to tumor angiogenesis by direct stimulation of the VEGF gene.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/sj.onc.1203817</identifier><identifier>PMID: 11030150</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>Basingstoke: Nature Publishing</publisher><subject>Angiogenesis ; Autocrine Communication ; Biological and medical sciences ; c-Myc protein ; Cancer ; Carcinoma, Squamous Cell - metabolism ; Carcinoma, Squamous Cell - pathology ; Carcinoma, Squamous Cell - virology ; Cell cycle ; Cell growth ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Cervical cancer ; Cervix ; Dysplasia ; E6 gene ; Endothelial cells ; Endothelial Growth Factors - genetics ; Endothelial Growth Factors - secretion ; ErbB-2 protein ; Female ; Fundamental and applied biological sciences. Psychology ; Genes, p53 ; Genetic engineering ; Genomes ; Health sciences ; HeLa Cells - metabolism ; HeLa Cells - secretion ; HeLa Cells - virology ; Human papillomavirus ; human papillomavirus 16 ; Humans ; Immortalization ; Invasiveness ; Keratinocytes ; Keratinocytes - virology ; Kinases ; Lymphokines - genetics ; Lymphokines - secretion ; Molecular and cellular biology ; Myc protein ; Neoplasm Proteins - physiology ; Neovascularization, Pathologic - genetics ; Neovascularization, Pathologic - physiopathology ; Oncogene Proteins, Viral - genetics ; Oncogene Proteins, Viral - physiology ; Oncogenes ; Oncoproteins ; p53 Protein ; Papillomaviridae - genetics ; Papillomaviridae - physiology ; Papillomavirus Infections - pathology ; Papillomavirus Infections - virology ; Promoter Regions, Genetic ; Proteins ; Receptor, Epidermal Growth Factor - physiology ; Recombinant Fusion Proteins - biosynthesis ; Reporter gene ; Repressor Proteins ; Transcription ; Transcription, Genetic ; Transcriptional Activation ; Transforming Growth Factor alpha - physiology ; Tumor Cells, Cultured - metabolism ; Tumor Cells, Cultured - secretion ; Tumor Cells, Cultured - virology ; Tumor Suppressor Protein p53 - physiology ; Tumor Virus Infections - pathology ; Tumor Virus Infections - virology ; Tumors ; Uterine Cervical Neoplasms - metabolism ; Uterine Cervical Neoplasms - pathology ; Uterine Cervical Neoplasms - virology ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; Vulvar Neoplasms - metabolism ; Vulvar Neoplasms - pathology ; Vulvar Neoplasms - virology</subject><ispartof>Oncogene, 2000-09, Vol.19 (40), p.4611-4620</ispartof><rights>2001 INIST-CNRS</rights><rights>COPYRIGHT 2000 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Sep 21, 2000</rights><rights>Macmillan Publishers Limited 2000.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c578t-adcc0ff3f70ae21d36a9b7cd8ec600aecf6d6d30e4176601957fcaf9253265443</citedby><cites>FETCH-LOGICAL-c578t-adcc0ff3f70ae21d36a9b7cd8ec600aecf6d6d30e4176601957fcaf9253265443</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=806902$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11030150$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LOPEZ-OCEJO, Omar</creatorcontrib><creatorcontrib>VILORIA-PETIT, Alicia</creatorcontrib><creatorcontrib>BEQUET-ROMERO, Monica</creatorcontrib><creatorcontrib>MUKHOPADHYAY, Debabrata</creatorcontrib><creatorcontrib>RAK, Janusz</creatorcontrib><creatorcontrib>KERBEL, Robert S</creatorcontrib><title>Oncogenes and tumor angiogenesis: The HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner</title><title>Oncogene</title><addtitle>Oncogene</addtitle><description>Like other types of pre-malignant lesions and carcinoma, angiogenesis is associated with high-grade cervical dysplasia and with invasive squamous carcinoma of the cervix. Vascular endothelial cell growth factor (VEGF) is known to be one of the most important inducers of angiogenesis and is upregulated in carcinoma of the cervix. Human Papilloma Virus 16 (HPV-16) has been etiologically linked to human cervical cancer, and the major oncogenic proteins encoded by the viral genome, E6 and E7, are involved in the immortalization of target cells. Because several oncogenes including mutant ras, EGF receptor, ErbB2/Her2, c-myc and v-src upregulate VEGF expression, we asked whether HVP-16 E6 oncoprotein could act in a similar fashion. We found that HPV-16 E6-positive cells generally express high levels of VEGF message. Furthermore, co-expression of the VEGF promoter-Luc (luciferase) reporter gene with E6 in both human keratinocytes and mouse fibroblast showed that E6 oncoprotein upregulates VEGF promoter activity, and does so in a p53 independent manner. An E6 responsive region which comprises four Sp-1 sites, between -194 and -50 bp of the VEGF promoter, is also necessary for constitutive VEGF transcription. Taken together, our results suggest the possibility that the HPV oncoprotein E6 may contribute to tumor angiogenesis by direct stimulation of the VEGF gene.</description><subject>Angiogenesis</subject><subject>Autocrine Communication</subject><subject>Biological and medical sciences</subject><subject>c-Myc protein</subject><subject>Cancer</subject><subject>Carcinoma, Squamous Cell - metabolism</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Carcinoma, Squamous Cell - virology</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cell physiology</subject><subject>Cell transformation and carcinogenesis. 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metabolism</topic><topic>Carcinoma, Squamous Cell - pathology</topic><topic>Carcinoma, Squamous Cell - virology</topic><topic>Cell cycle</topic><topic>Cell growth</topic><topic>Cell physiology</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Cervical cancer</topic><topic>Cervix</topic><topic>Dysplasia</topic><topic>E6 gene</topic><topic>Endothelial cells</topic><topic>Endothelial Growth Factors - genetics</topic><topic>Endothelial Growth Factors - secretion</topic><topic>ErbB-2 protein</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genes, p53</topic><topic>Genetic engineering</topic><topic>Genomes</topic><topic>Health sciences</topic><topic>HeLa Cells - metabolism</topic><topic>HeLa Cells - secretion</topic><topic>HeLa Cells - virology</topic><topic>Human papillomavirus</topic><topic>human papillomavirus 16</topic><topic>Humans</topic><topic>Immortalization</topic><topic>Invasiveness</topic><topic>Keratinocytes</topic><topic>Keratinocytes - virology</topic><topic>Kinases</topic><topic>Lymphokines - genetics</topic><topic>Lymphokines - secretion</topic><topic>Molecular and cellular biology</topic><topic>Myc protein</topic><topic>Neoplasm Proteins - physiology</topic><topic>Neovascularization, Pathologic - genetics</topic><topic>Neovascularization, Pathologic - physiopathology</topic><topic>Oncogene Proteins, Viral - genetics</topic><topic>Oncogene Proteins, Viral - physiology</topic><topic>Oncogenes</topic><topic>Oncoproteins</topic><topic>p53 Protein</topic><topic>Papillomaviridae - genetics</topic><topic>Papillomaviridae - 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Vascular endothelial cell growth factor (VEGF) is known to be one of the most important inducers of angiogenesis and is upregulated in carcinoma of the cervix. Human Papilloma Virus 16 (HPV-16) has been etiologically linked to human cervical cancer, and the major oncogenic proteins encoded by the viral genome, E6 and E7, are involved in the immortalization of target cells. Because several oncogenes including mutant ras, EGF receptor, ErbB2/Her2, c-myc and v-src upregulate VEGF expression, we asked whether HVP-16 E6 oncoprotein could act in a similar fashion. We found that HPV-16 E6-positive cells generally express high levels of VEGF message. Furthermore, co-expression of the VEGF promoter-Luc (luciferase) reporter gene with E6 in both human keratinocytes and mouse fibroblast showed that E6 oncoprotein upregulates VEGF promoter activity, and does so in a p53 independent manner. An E6 responsive region which comprises four Sp-1 sites, between -194 and -50 bp of the VEGF promoter, is also necessary for constitutive VEGF transcription. Taken together, our results suggest the possibility that the HPV oncoprotein E6 may contribute to tumor angiogenesis by direct stimulation of the VEGF gene.</abstract><cop>Basingstoke</cop><pub>Nature Publishing</pub><pmid>11030150</pmid><doi>10.1038/sj.onc.1203817</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Oncogene, 2000-09, Vol.19 (40), p.4611-4620 |
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| recordid | cdi_proquest_miscellaneous_72328838 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Angiogenesis Autocrine Communication Biological and medical sciences c-Myc protein Cancer Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - pathology Carcinoma, Squamous Cell - virology Cell cycle Cell growth Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cervical cancer Cervix Dysplasia E6 gene Endothelial cells Endothelial Growth Factors - genetics Endothelial Growth Factors - secretion ErbB-2 protein Female Fundamental and applied biological sciences. Psychology Genes, p53 Genetic engineering Genomes Health sciences HeLa Cells - metabolism HeLa Cells - secretion HeLa Cells - virology Human papillomavirus human papillomavirus 16 Humans Immortalization Invasiveness Keratinocytes Keratinocytes - virology Kinases Lymphokines - genetics Lymphokines - secretion Molecular and cellular biology Myc protein Neoplasm Proteins - physiology Neovascularization, Pathologic - genetics Neovascularization, Pathologic - physiopathology Oncogene Proteins, Viral - genetics Oncogene Proteins, Viral - physiology Oncogenes Oncoproteins p53 Protein Papillomaviridae - genetics Papillomaviridae - physiology Papillomavirus Infections - pathology Papillomavirus Infections - virology Promoter Regions, Genetic Proteins Receptor, Epidermal Growth Factor - physiology Recombinant Fusion Proteins - biosynthesis Reporter gene Repressor Proteins Transcription Transcription, Genetic Transcriptional Activation Transforming Growth Factor alpha - physiology Tumor Cells, Cultured - metabolism Tumor Cells, Cultured - secretion Tumor Cells, Cultured - virology Tumor Suppressor Protein p53 - physiology Tumor Virus Infections - pathology Tumor Virus Infections - virology Tumors Uterine Cervical Neoplasms - metabolism Uterine Cervical Neoplasms - pathology Uterine Cervical Neoplasms - virology Vascular endothelial growth factor Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Vulvar Neoplasms - metabolism Vulvar Neoplasms - pathology Vulvar Neoplasms - virology |
| title | Oncogenes and tumor angiogenesis: The HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-13T15%3A27%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Oncogenes%20and%20tumor%20angiogenesis:%20The%20HPV-16%20E6%20oncoprotein%20activates%20the%20vascular%20endothelial%20growth%20factor%20(VEGF)%20gene%20promoter%20in%20a%20p53%20independent%20manner&rft.jtitle=Oncogene&rft.au=LOPEZ-OCEJO,%20Omar&rft.date=2000-09-21&rft.volume=19&rft.issue=40&rft.spage=4611&rft.epage=4620&rft.pages=4611-4620&rft.issn=0950-9232&rft.eissn=1476-5594&rft.coden=ONCNES&rft_id=info:doi/10.1038/sj.onc.1203817&rft_dat=%3Cgale_proqu%3EA200416173%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=227306241&rft_id=info:pmid/11030150&rft_galeid=A200416173&rfr_iscdi=true |