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Journal of Virology, September 2003, p. 9852-9861, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.9852-9861.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Human Papillomavirus Type 16 E6 Activates TERT Gene Transcription through Induction of c-Myc and Release of USF-Mediated Repression

H. R. McMurray1 and D. J. McCance1,2*

Department of Microbiology and Immunology,1 The James P. Wilmot Cancer Center, University of Rochester, Rochester, New York 146422

Received 9 April 2003/ Accepted 14 June 2003

Human papillomavirus type 16 (HPV-16), a DNA tumor virus, has a causal role in cervical cancer, and the viral oncoproteins E6 and E7 contribute to oncogenesis in multiple ways. E6 increases telomerase activity in keratinocytes through increased transcription of the telomerase catalytic subunit gene (TERT), but the factors involved in this have been elusive. We have found that mutation of the proximal E box in the TERT promoter has an activating effect in luciferase assays. This suggested that a repressive complex might be present at this site. HPV-16 E6 activated the TERT promoter predominantly through the proximal E box, and thus, might be acting on this repressive complex. This site is specific for the Myc/Mad/Max transcription factors as well as USF1 and USF2. Addition of exogenous USF1 or USF2 repressed activation of the TERT promoter by E6, dependent on the proximal E box. Using siRNA against USF1 or USF2 allowed for greater activation of the TERT promoter by E6. Conversely, loss of c-Myc function, through a dominant-negative Myc molecule, reduced activation by E6. Chromatin immunoprecipitations showed that in the presence of E6, there was a reduction in binding of USF1 and USF2 at the TERT promoter proximal E box, and a concomitant increase in c-Myc bound to this site. This shows that a repressive complex containing USF1 and USF2 is present in normal cells with little or no telomerase activity. In E6 keratinocytes, this repressive complex is replaced by c-Myc, which corresponds to higher levels of TERT transcription and consequently, telomerase activity.

* Corresponding author. Mailing address: University of Rochester, School of Medicine and Dentistry, 601 Elmwood Ave., Box 672, Rochester, NY 14642. Phone: (585) 275-0101. Fax: (585) 473-9573. E-mail: dennis_mccance{at}urmc.rochester.edu.

Journal of Virology, September 2003, p. 9852-9861, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.9852-9861.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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