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Journal of Virology, November 2002, p. 11209-11215, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11209-11215.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

A Transactivator Function of Cottontail Rabbit Papillomavirus E2 Is Essential for Tumor Induction in Rabbits

Sonja Jeckel, Evamaria Huber, Frank Stubenrauch, and Thomas Iftner^*

Sektion Experimentelle Virologie, Universitätsklinikum Tübingen, 72076 Tübingen, Germany

Received 22 March 2002/ Accepted 30 July 2002

Infection of domestic rabbits with cottontail rabbit papillomavirus (CRPV) causes local papillomas which progress to carcinomas in more than 80% of cases. This animal model system therefore allows the identification of molecular mechanisms required for the induction and progression of epithelial tumors. The viral E2 protein stimulates both viral DNA replication and transcription, and these functions can be genetically separated. We introduced the respective mutations into CRPV E2 and found, in line with published data for other papillomavirus E2 proteins, that mutation of the highly conserved amino acid 37 or 73 resulted in replication-competent but transactivation-deficient E2 proteins, whereas E2 proteins with mutations at residue 39 were replication deficient and transactivation competent. The R37A, I73L, and I73A E2 mutants, showing a loss of transactivation function, and the R37K E2 mutant, which is still transactivation competent, were introduced into the whole genome of CRPV, which was then injected into the skin of rabbits. Strikingly, the ability to induce tumors within 6 weeks was abolished by each of the E2 mutations, in contrast to the tumor induction rate (93%) obtained with wild-type CRPV DNA. Two small papillomas induced by mutant E2 I73A CRPV DNA appeared as late as 12 or 24 weeks postinjection, were significantly smaller, and showed no further extension of growth. These data suggest that functionally conserved amino acids in the transactivation domain of E2 are also required for the induction and growth of epithelial tumors in rabbits infected with CRPV.

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* Corresponding author. Mailing address: Experimentelle Virologie, Universitätsklinikum Tübingen, Elfriede-Aulhorn Strasse 6, 72076 Tübingen, Germany. Phone: 49 7071 2980246. Fax: 49 7071 295419. E-mail: tsiftner{at}med.uni-tuebingen.de.

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Journal of Virology, November 2002, p. 11209-11215, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11209-11215.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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