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Journal of Virology, May 2003, p. 5253-5265, Vol. 77, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.9.5253-5265.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Papillomavirus E2 Protein Binds to and Synergizes with C/EBP Factors Involved in Keratinocyte Differentiation

Dirk Hadaschik, Korinna Hinterkeuser,{dagger} Monika Oldak, Herbert J. Pfister, and Sigrun Smola-Hess*

Institute of Virology, University of Cologne, 50935 Cologne, Germany

Received 16 September 2002/ Accepted 4 February 2003

The papillomavirus life cycle is closely linked to the differentiation program of the host keratinocyte. Thus, late gene expression and viral maturation are restricted to terminally differentiated keratinocytes. A variety of cellular transcription factors including those of the C/EBP family are involved in the regulation of keratinocyte differentiation. In this study we show that the papillomavirus transcription factor E2 cooperates with C/EBP{alpha} and -ß in transcriptional activation. This synergism was independent of an E2 binding site. E2 and C/EBP factors synergistically transactivated a synthetic promoter construct containing classical C/EBPß sites and the C/EBP{alpha}-responsive proximal promoter of the involucrin gene, which is naturally expressed in differentiating keratinocytes. C/EBP{alpha} or -ß coprecipitated with E2 proteins derived from human papillomavirus type 8 (HPV8), HPV16, HPV18, and bovine papillomavirus type 1 in vitro and in vivo, indicating complex formation by the cellular and viral factors. The interaction domains could be mapped to the C terminus of E2 and amino acids 261 to 302 located within the bZIP motif of C/EBPß. Our data suggest that E2, via its interaction with C/EBP factors, may contribute to enhancing keratinocyte differentiation, which is suppressed by the viral oncoproteins E6 and E7 in HPV-induced lesions.

* Corresponding author. Mailing address: Institute of Virology, University of Cologne, Fürst-Pückler-Str. 56, 50935 Cologne, Germany. Phone: 49-221-478-3928. Fax: 49-221-478-3902. E-mail: s.smola{at}uni-koeln.de.

{dagger} Present address: Verigen AG, 51377 Leverkusen, Germany.

Journal of Virology, May 2003, p. 5253-5265, Vol. 77, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.9.5253-5265.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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