Prevalence of deletions of YY1-binding sites in episomal HPV 16 DNA from cervical cancers.
Expression of the oncogenes E6 and E7 of human papillomavirus 16 (HPV 16) appears enhanced in pre-malignant and malignant genital tumors. We recently identified a transcriptional silencer upstream of the oncogene promoter P97, comprising 4 binding sites for the cellular YY1 protein. The analysis of the long transcriptional control regions (LCR) of episomal HPV 16 DNAs from primary tumors and lymph-node metastases of 6 patients with cervical cancer revealed deletions and point mutations of YY1 binding sites in 4 cases. To test for the activity of the P97 promoter, the mutated LCRs were cloned in a luciferase reporter gene vector. A point mutation in YY1-recognition site 4, which prevents DNA-protein interaction, did not affect promoter activity, probably due to compensation by the overlapping YY1-binding site 3. However, 5.5- to 6.5-fold increased luciferase expression was obtained under the control of 3 shortened LCRs lacking 2 to 4 YY1-binding sites. A point mutation in YY1-recognition site 2, which was previously shown to stimulate P97 3.5-fold, could be detected in the HPV 16 LCRs from both primary tumor and metastasis, indicating that the mutation is a stable characteristic of HPV 16 DNA associated with the individual cancer. These findings suggest that deletions or mutations of YY1-binding sites play a significant role in over-expression of viral oncogenes and tumor progression.
Dong
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Institut für Klinische und Molekulare Virologie, Universität Erlangen-Nürnberg, Germany.
Stubenrauch
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Beyer-Finkler
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Pfister
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D001483:Base Sequence; D001665:Binding Sites; D015139:Blotting, Southern; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000821:virology*; D004279:DNA, Viral / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D027383:Papillomaviridae / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000821:virology*; D050986:YY1 Transcription Factor
D004279:DNA, Viral; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D050981:Erythroid-Specific DNA-Binding Factors; D009856:Oncogene Proteins, Viral; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human