Differential disruption of genomic integrity and cell cycle regulation in normal human fibroblasts by the HPV oncoproteins.
Genomic integrity is maintained by a network of cellular activities that assess the status of the genome at a given point in time, provide signals to proceed with or halt cell cycle progression, and provide for repair of damaged DNA. Mutations in any part of these pathways can have the ultimate effect of disturbing chromosomal integrity. Recent work suggests that p53 performs this integrator function in mammalian cells. Our present study demonstrates that in mortal cells, the expression of E6 and E7 viral oncoproteins of type 16 human papillomavirus each disrupts the integration of these signals by diverged pathways. Cells expressing E6 protein, which binds and degrades the p53 protein, exhibited alterations in cell cycle control when placed in drug and displayed the ability to amplify the CAD gene. The expression of E7, which binds different cellular proteins important for transformation, including Rb, led to a p53-independent alteration in cell cycle control, a widespread cytocidal response, and polyploidy as a mechanism of drug resistance. These results demonstrate that diverse perturbations of molecular pathways can have different effects on chromosomal integrity.
White
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Lineberger Comprehensive Cancer Center, Department of Pathology, University of North Carolina at Chapel Hill, School of Medicine 27599-7295.
Livanos
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Tlsty
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D000970:Antineoplastic Agents / Q000494:pharmacology; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005784:Gene Amplification; D005822:Genetic Vectors; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000502:physiology*; D016366:Open Reading Frames; D027383:Papillomaviridae / Q000235:genetics / Q000502:physiology*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000970:Antineoplastic Agents; D009856:Oncogene Proteins, Viral; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D001224:Aspartic Acid; C013195:sparfosic acid; D010746:Phosphonoacetic Acid