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J Virol, July 1998, p. 6175-6180, Vol. 72, No. 7
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Woodchuck Hepatitis Virus Enhancer I and Enhancer II Are Both Involved in N-myc2 Activation in Woodchuck Liver Tumors

Marc Flajolet, Pierre Tiollais, Marie-Annick Buendia, and Geneviève Fourel^*

Unité de Recombinaison et Expression Génétique, INSERM U163, Institut Pasteur, 75724 Paris Cedex 15, France

Received 8 December 1997/Accepted 25 March 1998

Direct activation of the N-myc2 oncogene by insertion of woodchuck hepatitis virus (WHV) DNA is a major oncogenic step in woodchuck hepatocarcinogenesis. We previously reported that WHV enhancer II (We2), which controls expression of the core/pregenome RNA, can also activate the N-myc2 promoter in hepatoma cell lines. To better define the integrated WHV regulatory sequences responsible for N-myc2 promoter activation in woodchuck liver tumors, we analyzed the structure and enhancer activity of a single viral integrant found at the win locus in tumor 2260T1 and mapping approximately 175 kb 3' of N-myc2. This viral insert was made of 11 concatemerized WHV fragments, 5 of which overlapped with We2 sequences and 1 with WHV sequence homologous to that of hepatitis B virus enhancer I (We1). In transient transfection assays in hepatoma-derived cells, the We2 activator was found to be fully effective only when inserted in close proximity to the N-myc2 promoter whereas the We1 element by itself was apparently devoid of activity. In contrast, the 2260T1 viral insert exhibited a potent enhancer capacity that depended both on multimerized We2 and on We1 sequences. In a survey of different woodchuck hepatomas, both elements were commonly found within integrated viral sequences involved in long-range N-myc2 activation.

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^* Corresponding author. Present address: CNRS UMR 49, Ecole Normale Supérieure de Lyon, 46 Allée d'Italie, 69634 Lyon Cedex 07, France. Phone: 33-4 72 72 84 53. Fax: 33-4 72 72 86 86. E-mail: Genevieve.Fourel{at}ens-lyon.fr.

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J Virol, July 1998, p. 6175-6180, Vol. 72, No. 7
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

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