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J. Biol. Chem., Vol. 278, Issue 39, 37306-37313, September 26, 2003

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Tyrphostin AG 555 Inhibits Bovine Papillomavirus Transcription by Changing the Ratio between E2 Transactivator/Repressor Function^*

Sabine Baars , Anastasia Bachmann , Alexander Levitzki  and Frank Rösl  ¶

From the Angewandte Tumorvirologie, Abteilung Virale Transformationsmechanismen, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, Heidelberg 69120, Germany and the Department of Biological Chemistry, The Hebrew University, 91904 Jerusalem, Israel

The tyrosine kinase inhibitor (tyrphostin) AG 555 selectively interferes with viral transcription in bovine papillomavirus type 1 (BPV-1)-transformed fibroblasts and induces suppression of cyclin-dependent kinase activity and cell cycle arrest. Concomitant with inhibition of viral transcription, c-Jun was strongly up-regulated, which was consistent with the observation that AG 555 treatment also led to an activation of the mitogen-activated protein kinase pathway by enhancing phosphorylation of JNK and p38. Increased JNK and p38 activity resulted in higher phosphorylation of the AP-1 family members c-Jun and activating transcription factor 2. Scanning the BPV-1 genome for potential binding sequences, an intragenic AP-1 site (BAP-1) within the E7 open reading frame was detected. Enhanced dimerization of phosphorylated activating transcription factor 2 together with c-Jun and binding to BAP-1 seem to be responsible for viral dysregulation because both suppression of BPV-1 and induction of c-Jun mRNA could be almost entirely abrogated by simultaneous treatment with SB 203580, an inhibitor of p38 mitogen-activated protein kinase activity. Moreover, dissecting the complex transcriptional pattern of episomal BPV-1 with specific primer sets for reverse transcription-PCR analysis, the repressive effect could be attributed to a selective down-regulation of the mRNA encoding the E2 transactivator function in favor of the E2 repressor, whose mRNA level remained constant during AG 555 treatment. These data indicate that tyrphostin AG 555 disturbs the balance of negative and positive regulatory factors necessary to maintain the homeostasis of a virus-transformed phenotype.

Received for publication, April 29, 2003 , and in revised form, June 26, 2003.

^* This work was supported by the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum and the Israeli Ministry of Science. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Abteilung Virale Transformationsmechanismen, Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Angewandte Tumorvirologie, Im Neuenheimer Feld 242, Heidelberg 69120, Germany. Tel.: 49-6221-42-4900; Fax: 49-6221-42-4902; E-mail: f.roesl{at}dkfz.de.

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