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Inhibition of human papillomavirus-16 long control region activity by interferon-gamma overcome by p300 overexpression

par Fontaine, Véronique ;van der Meijden, E;ter Schegget, J
Référence Molecular carcinogenesis, 31, 1, page (27-36)
Publication Publié, 2001-05

Article révisé par les pairs

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Résumé :

Although interferons (IFNs) are currently used in the treatment of various human papillomavirus (HPV)-associated lesions, their mechanisms of action are still unclear. In this study, we clearly demonstrated that IFN-gamma was a strong inhibitor of HPV-16 long control region (LCR) activity in two human cervical carcinoma cell lines. The effect of IFN-gamma was dose dependent. We investigated whether the effect of IFN-gamma on HPV-16 LCR could involve the inhibition of the CREB-binding protein (CBP)/p300 family of transcriptional coactivators. In support of this model, we demonstrated by transfection experiments that a 12S E1A mutant (RG2), which interacts poorly with p300 and CBP in comparison to wild-type E1A, was less able to repress human papillomavirus (HPV) 16 long control region (LCR) than wild-type E1A. More important, overexpression of p300 was able to increase the HPV-16 LCR activity and to overcome inhibition by IFN-gamma. Finally, we demonstrated that p300 could cooperate with c-jun to activate HPV-16 LCR. According to our results, IFN-gamma might inhibit HPV-16 LCR transcription by activating the signal transducer and activator of transcription 1alpha, which in turn might compete for p300/CBP binding with specific transcription factors involved in LCR activation.