Clonal selection for transcriptionally active viral oncogenes during progression to cancer

Brian A. Van Tine, John C. Kappes, N. Sanjib Banerjee, Judith Knops, Lilin Lai, Renske D.M. Steenbergen, Chris L.J.M. Meijer, Peter J.F. Snijders, Pamela Chatis, Thomas R. Broker, Phillip T. Moen, Louise T. Chow

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Primary keratinocytes immortalized by human papillomaviruses (HPVs), along with HPV-induced cervical carcinoma cell lines, are excellent models for investigating neoplastic progression to cancer. By simultaneously visualizing viral DNA and nascent viral transcripts in interphase nuclei, we demonstrated for the first time a selection for a single dominant papillomavirus transcription center or domain (PVTD) independent of integrated viral DNA copy numbers or loci. The PVTD did not associate with several known subnuclear addresses but was almost always perinucleolar. Silent copies of the viral genome were activated by growth in the DNA methylation inhibitor 5-azacytidine. HPV-immortalized keratinocytes supertransduced with HPV oncogenes and selected for marker gene coexpression underwent crisis, and the surviving cells transcribed only the newly introduced genes. Thus, transcriptional selection in response to environmental changes is a dynamic process to achieve optimal gene expression for cell survival. This phenomenon may be critical in clonal selection during carcinogenesis. Examination of HPV-associated cancers supports this hypothesis.

Original languageEnglish
Pages (from-to)11172-11186
Number of pages15
JournalJournal of virology
Volume78
Issue number20
DOIs
StatePublished - Oct 2004

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