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Differential splicing of E6 within human papillomavirus type 18 variants and functional consequences
1 Unit of Biomedical Research in Cancer, National Cancer Institute/Biomedical Research Institute, National Autonomous University of Mexico, Av. San Fernando No. 22, Col. Sección 16, Tlalpan, 14080 Mexico City, Mexico 2 Department of Pathology, National Cancer Institute, Mexico City, Mexico Correspon...
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| Published in: | Journal of general virology 2005-09, Vol.86 (9), p.2459-2468 |
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| creator | De la Cruz-Hernandez, Erick Garcia-Carranca, Alejandro Mohar-Betancourt, Alejandro Duenas-Gonzalez, Alfonso Contreras-Paredes, Adriana Perez-Cardenas, Enrique Herrera-Goepfert, Roberto Lizano-Soberon, Marcela |
| description | 1 Unit of Biomedical Research in Cancer, National Cancer Institute/Biomedical Research Institute, National Autonomous University of Mexico, Av. San Fernando No. 22, Col. Sección 16, Tlalpan, 14080 Mexico City, Mexico
2 Department of Pathology, National Cancer Institute, Mexico City, Mexico
Correspondence Marcela Lizano-Soberón lizano{at}servidor.unam.mx
Persistent infections of the uterine cervix with high-risk human papillomavirus (HPV) are now recognized as necessary for the development of cervical cancer. Among them, HPV types 16 and 18 exhibit numerous variants associated with different risks for cervical cancer development. In this study, the questions of whether different HPV type 18 variants exhibit changes in early gene transcription and the molecular mechanisms underlying these differences were investigated. It was shown that, indeed, type 18 variants exhibited singular differences in E6 transcripts in vivo . Higher levels of the E6*I transcript were detected regularly in clones harbouring the African variant, as opposed to low levels of this transcript detected in clones containing the reference clone (AsianAmerindian), where significantly higher levels of full-length E6 transcript were usually observed. As a direct consequence, higher levels of p53 protein were found in the presence of African E6, as opposed to the low levels of p53 observed with the AsianAmerindian E6. These variations in consequence affected the levels of cellular proteins regulated by p53, such as Bax. Similar changes in the relative levels of E6 transcripts were observed when tumours containing type 18 E6 variants were analysed. The different ability of cells containing variant E6 genes to form tumours in nude mice was suggested by the fact that tumour volumes were considerably higher when cells expressed the AsianAmerindian E6. Mutagenesis analysis of the reference clone showed that a C491A change reverts the phenotype. These results suggest that different splicing patterns of E6 within HPV type 18 variants may possibly have biological implications in viral tumorigenesis. |
| doi_str_mv | 10.1099/vir.0.80945-0 |
| format | article |
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2 Department of Pathology, National Cancer Institute, Mexico City, Mexico
Correspondence Marcela Lizano-Soberón lizano{at}servidor.unam.mx
Persistent infections of the uterine cervix with high-risk human papillomavirus (HPV) are now recognized as necessary for the development of cervical cancer. Among them, HPV types 16 and 18 exhibit numerous variants associated with different risks for cervical cancer development. In this study, the questions of whether different HPV type 18 variants exhibit changes in early gene transcription and the molecular mechanisms underlying these differences were investigated. It was shown that, indeed, type 18 variants exhibited singular differences in E6 transcripts in vivo . Higher levels of the E6*I transcript were detected regularly in clones harbouring the African variant, as opposed to low levels of this transcript detected in clones containing the reference clone (AsianAmerindian), where significantly higher levels of full-length E6 transcript were usually observed. As a direct consequence, higher levels of p53 protein were found in the presence of African E6, as opposed to the low levels of p53 observed with the AsianAmerindian E6. These variations in consequence affected the levels of cellular proteins regulated by p53, such as Bax. Similar changes in the relative levels of E6 transcripts were observed when tumours containing type 18 E6 variants were analysed. The different ability of cells containing variant E6 genes to form tumours in nude mice was suggested by the fact that tumour volumes were considerably higher when cells expressed the AsianAmerindian E6. Mutagenesis analysis of the reference clone showed that a C491A change reverts the phenotype. These results suggest that different splicing patterns of E6 within HPV type 18 variants may possibly have biological implications in viral tumorigenesis.</description><identifier>ISSN: 0022-1317</identifier><identifier>EISSN: 1465-2099</identifier><identifier>DOI: 10.1099/vir.0.80945-0</identifier><identifier>PMID: 16099904</identifier><identifier>CODEN: JGVIAY</identifier><language>eng</language><publisher>Reading: Soc General Microbiol</publisher><subject>Animals ; Biological and medical sciences ; Cell Line ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Female ; Fundamental and applied biological sciences. Psychology ; Genetic Variation ; HeLa Cells ; Human papillomavirus 18 ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Microbiology ; Miscellaneous ; NIH 3T3 Cells ; Oncogene Proteins, Viral - genetics ; Oncogene Proteins, Viral - metabolism ; Papillomaviridae - classification ; Papillomaviridae - genetics ; Papillomaviridae - pathogenicity ; Papillomavirus Infections - physiopathology ; Papillomavirus Infections - virology ; RNA Splicing ; Uterine Cervical Neoplasms - physiopathology ; Uterine Cervical Neoplasms - virology ; Virology</subject><ispartof>Journal of general virology, 2005-09, Vol.86 (9), p.2459-2468</ispartof><rights>2005 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c424t-6ead1dd6826626075a79091c205343f81de994b8fa5c11ca44a2588902bebef3</citedby><cites>FETCH-LOGICAL-c424t-6ead1dd6826626075a79091c205343f81de994b8fa5c11ca44a2588902bebef3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17021471$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16099904$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>De la Cruz-Hernandez, Erick</creatorcontrib><creatorcontrib>Garcia-Carranca, Alejandro</creatorcontrib><creatorcontrib>Mohar-Betancourt, Alejandro</creatorcontrib><creatorcontrib>Duenas-Gonzalez, Alfonso</creatorcontrib><creatorcontrib>Contreras-Paredes, Adriana</creatorcontrib><creatorcontrib>Perez-Cardenas, Enrique</creatorcontrib><creatorcontrib>Herrera-Goepfert, Roberto</creatorcontrib><creatorcontrib>Lizano-Soberon, Marcela</creatorcontrib><title>Differential splicing of E6 within human papillomavirus type 18 variants and functional consequences</title><title>Journal of general virology</title><addtitle>J Gen Virol</addtitle><description>1 Unit of Biomedical Research in Cancer, National Cancer Institute/Biomedical Research Institute, National Autonomous University of Mexico, Av. San Fernando No. 22, Col. Sección 16, Tlalpan, 14080 Mexico City, Mexico
2 Department of Pathology, National Cancer Institute, Mexico City, Mexico
Correspondence Marcela Lizano-Soberón lizano{at}servidor.unam.mx
Persistent infections of the uterine cervix with high-risk human papillomavirus (HPV) are now recognized as necessary for the development of cervical cancer. Among them, HPV types 16 and 18 exhibit numerous variants associated with different risks for cervical cancer development. In this study, the questions of whether different HPV type 18 variants exhibit changes in early gene transcription and the molecular mechanisms underlying these differences were investigated. It was shown that, indeed, type 18 variants exhibited singular differences in E6 transcripts in vivo . Higher levels of the E6*I transcript were detected regularly in clones harbouring the African variant, as opposed to low levels of this transcript detected in clones containing the reference clone (AsianAmerindian), where significantly higher levels of full-length E6 transcript were usually observed. As a direct consequence, higher levels of p53 protein were found in the presence of African E6, as opposed to the low levels of p53 observed with the AsianAmerindian E6. These variations in consequence affected the levels of cellular proteins regulated by p53, such as Bax. Similar changes in the relative levels of E6 transcripts were observed when tumours containing type 18 E6 variants were analysed. The different ability of cells containing variant E6 genes to form tumours in nude mice was suggested by the fact that tumour volumes were considerably higher when cells expressed the AsianAmerindian E6. Mutagenesis analysis of the reference clone showed that a C491A change reverts the phenotype. These results suggest that different splicing patterns of E6 within HPV type 18 variants may possibly have biological implications in viral tumorigenesis.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetic Variation</subject><subject>HeLa Cells</subject><subject>Human papillomavirus 18</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Microbiology</subject><subject>Miscellaneous</subject><subject>NIH 3T3 Cells</subject><subject>Oncogene Proteins, Viral - genetics</subject><subject>Oncogene Proteins, Viral - metabolism</subject><subject>Papillomaviridae - classification</subject><subject>Papillomaviridae - genetics</subject><subject>Papillomaviridae - pathogenicity</subject><subject>Papillomavirus Infections - physiopathology</subject><subject>Papillomavirus Infections - virology</subject><subject>RNA Splicing</subject><subject>Uterine Cervical Neoplasms - physiopathology</subject><subject>Uterine Cervical Neoplasms - virology</subject><subject>Virology</subject><issn>0022-1317</issn><issn>1465-2099</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><recordid>eNpF0LFP3DAYBXCrKoKDMnatvLRiyfWzYzvxiCgFJKQu7NYXx75zlTjBTkD89zW9k5g8-Kf37EfIVwZbBlr_fAlpC9sWtJAVfCIbJpSseLn5TDYAnFesZs0ZOc_5LwATQjan5IypAjSIDel_Be9dcnEJONA8D8GGuKOTp7eKvoZlHyLdryNGOuMchmEasTSumS5vs6OspS-YAsYlU4w99Wu0S5hiibJTzO55ddG6_IWceByyuzyeF-Tp9-3TzX31-Ofu4eb6sbKCi6VSDnvW96rlSnEFjcRGg2aWg6xF7VvWO61F13qUljGLQiCXbauBd65zvr4gPw6xc5pKc17MGLJ1w4DRTWs2rJFCK64LrA7Qpinn5LyZUxgxvRkG5n1VU_5owPxf1UDx347Baze6_kMfZyzg-xFgtjj4hNGG_OEa4Ew0rLirg9uH3f41JGd2Lo6hPKML03tpq4w2XEhd_wM71480</recordid><startdate>20050901</startdate><enddate>20050901</enddate><creator>De la Cruz-Hernandez, Erick</creator><creator>Garcia-Carranca, Alejandro</creator><creator>Mohar-Betancourt, Alejandro</creator><creator>Duenas-Gonzalez, Alfonso</creator><creator>Contreras-Paredes, Adriana</creator><creator>Perez-Cardenas, Enrique</creator><creator>Herrera-Goepfert, Roberto</creator><creator>Lizano-Soberon, Marcela</creator><general>Soc General Microbiol</general><general>Society for General Microbiology</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U9</scope><scope>H94</scope></search><sort><creationdate>20050901</creationdate><title>Differential splicing of E6 within human papillomavirus type 18 variants and functional consequences</title><author>De la Cruz-Hernandez, Erick ; Garcia-Carranca, Alejandro ; Mohar-Betancourt, Alejandro ; Duenas-Gonzalez, Alfonso ; Contreras-Paredes, Adriana ; Perez-Cardenas, Enrique ; Herrera-Goepfert, Roberto ; Lizano-Soberon, Marcela</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c424t-6ead1dd6826626075a79091c205343f81de994b8fa5c11ca44a2588902bebef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genetic Variation</topic><topic>HeLa Cells</topic><topic>Human papillomavirus 18</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Microbiology</topic><topic>Miscellaneous</topic><topic>NIH 3T3 Cells</topic><topic>Oncogene Proteins, Viral - genetics</topic><topic>Oncogene Proteins, Viral - metabolism</topic><topic>Papillomaviridae - classification</topic><topic>Papillomaviridae - genetics</topic><topic>Papillomaviridae - pathogenicity</topic><topic>Papillomavirus Infections - physiopathology</topic><topic>Papillomavirus Infections - virology</topic><topic>RNA Splicing</topic><topic>Uterine Cervical Neoplasms - physiopathology</topic><topic>Uterine Cervical Neoplasms - virology</topic><topic>Virology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>De la Cruz-Hernandez, Erick</creatorcontrib><creatorcontrib>Garcia-Carranca, Alejandro</creatorcontrib><creatorcontrib>Mohar-Betancourt, Alejandro</creatorcontrib><creatorcontrib>Duenas-Gonzalez, Alfonso</creatorcontrib><creatorcontrib>Contreras-Paredes, Adriana</creatorcontrib><creatorcontrib>Perez-Cardenas, Enrique</creatorcontrib><creatorcontrib>Herrera-Goepfert, Roberto</creatorcontrib><creatorcontrib>Lizano-Soberon, Marcela</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Journal of general virology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>De la Cruz-Hernandez, Erick</au><au>Garcia-Carranca, Alejandro</au><au>Mohar-Betancourt, Alejandro</au><au>Duenas-Gonzalez, Alfonso</au><au>Contreras-Paredes, Adriana</au><au>Perez-Cardenas, Enrique</au><au>Herrera-Goepfert, Roberto</au><au>Lizano-Soberon, Marcela</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Differential splicing of E6 within human papillomavirus type 18 variants and functional consequences</atitle><jtitle>Journal of general virology</jtitle><addtitle>J Gen Virol</addtitle><date>2005-09-01</date><risdate>2005</risdate><volume>86</volume><issue>9</issue><spage>2459</spage><epage>2468</epage><pages>2459-2468</pages><issn>0022-1317</issn><eissn>1465-2099</eissn><coden>JGVIAY</coden><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>1 Unit of Biomedical Research in Cancer, National Cancer Institute/Biomedical Research Institute, National Autonomous University of Mexico, Av. San Fernando No. 22, Col. Sección 16, Tlalpan, 14080 Mexico City, Mexico
2 Department of Pathology, National Cancer Institute, Mexico City, Mexico
Correspondence Marcela Lizano-Soberón lizano{at}servidor.unam.mx
Persistent infections of the uterine cervix with high-risk human papillomavirus (HPV) are now recognized as necessary for the development of cervical cancer. Among them, HPV types 16 and 18 exhibit numerous variants associated with different risks for cervical cancer development. In this study, the questions of whether different HPV type 18 variants exhibit changes in early gene transcription and the molecular mechanisms underlying these differences were investigated. It was shown that, indeed, type 18 variants exhibited singular differences in E6 transcripts in vivo . Higher levels of the E6*I transcript were detected regularly in clones harbouring the African variant, as opposed to low levels of this transcript detected in clones containing the reference clone (AsianAmerindian), where significantly higher levels of full-length E6 transcript were usually observed. As a direct consequence, higher levels of p53 protein were found in the presence of African E6, as opposed to the low levels of p53 observed with the AsianAmerindian E6. These variations in consequence affected the levels of cellular proteins regulated by p53, such as Bax. Similar changes in the relative levels of E6 transcripts were observed when tumours containing type 18 E6 variants were analysed. The different ability of cells containing variant E6 genes to form tumours in nude mice was suggested by the fact that tumour volumes were considerably higher when cells expressed the AsianAmerindian E6. Mutagenesis analysis of the reference clone showed that a C491A change reverts the phenotype. These results suggest that different splicing patterns of E6 within HPV type 18 variants may possibly have biological implications in viral tumorigenesis.</abstract><cop>Reading</cop><pub>Soc General Microbiol</pub><pmid>16099904</pmid><doi>10.1099/vir.0.80945-0</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological and medical sciences Cell Line DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Female Fundamental and applied biological sciences. Psychology Genetic Variation HeLa Cells Human papillomavirus 18 Humans Mice Mice, Inbred BALB C Mice, Nude Microbiology Miscellaneous NIH 3T3 Cells Oncogene Proteins, Viral - genetics Oncogene Proteins, Viral - metabolism Papillomaviridae - classification Papillomaviridae - genetics Papillomaviridae - pathogenicity Papillomavirus Infections - physiopathology Papillomavirus Infections - virology RNA Splicing Uterine Cervical Neoplasms - physiopathology Uterine Cervical Neoplasms - virology Virology |
| title | Differential splicing of E6 within human papillomavirus type 18 variants and functional consequences |
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