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Journal of Virology, October 2004, p. 11172-11186, Vol. 78, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.20.11172-11186.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Clonal Selection for Transcriptionally Active Viral Oncogenes during Progression to Cancer

Brian A. Van Tine,^1,2 John C. Kappes,^3,4 N. Sanjib Banerjee,² Judith Knops,^5, Lilin Lai,³ Renske D. M. Steenbergen,⁶ Chris L. J. M. Meijer,⁶ Peter J. F. Snijders,⁶ Pamela Chatis,^7,8 Thomas R. Broker,² Phillip T. Moen Jr.,^7, and Louise T. Chow^2*

Department of Pathology,¹ Department of Biochemistry and Molecular Genetics,² Department of Medicine,³ Department of Microbiology,⁴ Laboratory of Medical Genetics University of Alabama at Birmingham, Birmingham, Alabama,⁵ Department of Pathology, Vrije Universitat Medical Center, Boelelaan, Amsterdam, The Netherlands,⁶ New Technologies Research and Development Group, Perkin-Elmer Life Sciences, Inc.,⁷ Division of Infectious Disease, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, Massachusetts⁸

Received 30 April 2004/ Accepted 16 June 2004

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.

Present address: Genzyme Genetics, Santa Fe, NM 87505.

Present address: One Cell Systems, Inc., Cambridge, MA 02139.

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