title: p53-independent growth regulation of cervical cancer cells by the papillomavirus E6 oncogene.
abstract: Growth of cervical carcinoma cells depends on continuous expression of high risk type human papillomavirus oncogenes E6 and E7. E6 destabilizes p53, a tumor-suppressive transcription factor, which activates expression of the inhibitor of cell cycle progression p21 and other genes. E6-mediated p53 degradation can therefore result in cell cycle deregulation. It has, however, not yet been determined whether p53 inactivation is sufficient to provoke cell cycle progression in established cervical carcinoma cells. Moreover, it has not yet been clarified whether E6 confers additional p53-independent growth stimuli in cancer cells. To address these questions, we analysed p53 functions in SW 756 cervical cancer cells in which the expression of endogenous HPV 18 E6-E7 genes can be downregulated by dexamethasone. This results in significantly increased p53 levels and subsequent cell cycle arrest in the Gz phase. Surprisingly, p53 activities were suppressed rather than enhanced in these cervical cancer cells. However, if high risk papillomavirus type 16 E6 genes, including a mutant which does not degrade p53, were expressed in dexamethasone-treated SW 756 cells with suppressed endogenous HPV type 18 E6-E7 expression, the cells reentered the cell cycle even in the absence of a cooperating viral E7 gene. In contrast, the non oncogenic papillomavirus type 6 E6 gene did not release the cells from growth arrest under these conditions. These data indicate that suppression of p53 functions is not sufficient to provoke cell cycle progression in E6-E7-depleted cervical cancer cells and point to a p53-independent mitotic activity to oncogenic papillomavirus type E6 genes in cervical carcinoma cells.
authors.affiliation: FSP6 Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Spitkovsky
authors.forename: F
authors.initials: F
authors.lastname: Aengeneyndt
authors.forename: J
authors.initials: J
authors.lastname: Braspenning
authors.forename: M
authors.initials: M
authors.lastname: von Knebel Doeberitz
mesh_terms: D000595:Amino Acid Sequence; D002277:Carcinoma / Q000235:genetics / Q000473:pathology / Q000821:virology; D002453:Cell Cycle / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002999:Clone Cells; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004268:DNA-Binding Proteins; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D016193:G1 Phase / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D017930:Genes, Reporter; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000235:genetics*; D010957:Plasmids / Q000235:genetics; D012097:Repressor Proteins; D015534:Trans-Activators; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D003907:Dexamethasone