Inhibition of human papillomavirus-16 long control region activity by interferon-gamma overcome by p300 overexpression.
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.
Fontaine
V
V
Department of Virology, Academisch Medisch Centrum, University of Amsterdam, Amsterdam, The Netherlands.
van der Meijden
E
E
ter Schegget
J
J
D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004279:DNA, Viral / Q000032:analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005814:Genes, Viral / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000821:virology
D017500:Adenovirus E1A Proteins; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D007371:Interferon-gamma; D008156:Luciferases