This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huang, S.-M. Articles by McCance, D. J. Search for Related Content PubMed PubMed Citation Articles by Huang, S.-M. Articles by McCance, D. J.

Down Regulation of the Interleukin-8 Promoter by Human Papillomavirus Type 16 E6 and E7 through Effects on CREB Binding Protein/p300 and P/CAF

Department of Microbiology and Immunology,¹ The Cancer Center, University of Rochester, Rochester, New York 14642²

Received 5 March 2002/ Accepted 6 June 2002

Previously, we reported that human papillomavirus (HPV) type 16 E6 binds to C/H1, C/H3, and the C-terminal domains of coactivators p300 and CBP, causing the modulation of the transcription of certain genes controlled by NF-B (p65 or relA) and p53. To establish the biological significance of these observations, we have focused on the transcriptional regulation of interleukin-8 (IL-8), a potent chemoattractant for T lymphocytes and neutrophils, which is also essential for the initiation of the local immune response. The IL-8 promoter is regulated by NF-B/p65 in response to tumor necrosis factor alpha and requires the cooperation of the coactivators CBP/p300 and steroid receptor coactivator 1 (SRC-1) and the p300/CBP-associated factor (P/CAF) for optimal activation. Here we report that, in the presence of HPV-16 E6, the promoter activity of IL-8 was repressed. Moreover, from the mutational analysis of the IL-8 promoter, we found that E6 down-regulates the IL-8 promoter activity through the NF-B/p65 binding site. This inhibition appears to result from the ability of HPV-16 E6 to compete with NF-B/p65 and SRC-1 for binding to the N terminus and C terminus of CBP, respectively. Reporter data also showed that E7 represses IL-8 promoter activity, though to a lesser extent than E6 but, like E6, the repression by E7 is through the NF-B/p65 binding site. E7 was shown for the first time to bind to P/CAF, and the binding was necessary for the down regulation of the IL-8 promoter. E6 and E7 together inhibited transcription of the IL-8 promoter to a greater extent than either alone. Finally, by RNase protection assay, we showed that the synthesis of endogenous IL-8 mRNA was repressed in keratinocytes stably expressing E6 and E7. Taken together, the results provide evidence that E6 and E7 can cooperatively disrupt IL-8 transcription through disruption of transcriptional active complexes, and this may have important consequences for immune responses in infected hosts.

This article has been cited by other articles:

• Schmeck, B., Lorenz, J., N'Guessan, P. D., Opitz, B., van Laak, V., Zahlten, J., Slevogt, H., Witzenrath, M., Flieger, A., Suttorp, N., Hippenstiel, S. (2008). Histone Acetylation and Flagellin Are Essential for Legionella pneumophila-Induced Cytokine Expression. J. Immunol. 181: 940-947 [Abstract] [Full Text]  
• Muller-Schiffmann, A., Beckmann, J., Steger, G. (2006). The e6 protein of the cutaneous human papillomavirus type 8 can stimulate the viral early and late promoters by distinct mechanisms.. J. Virol. 80: 8718-8728 [Abstract] [Full Text]  
• Baldwin, A., Huh, K.-W., Munger, K. (2006). Human papillomavirus e7 oncoprotein dysregulates steroid receptor coactivator 1 localization and function.. J. Virol. 80: 6669-6677 [Abstract] [Full Text]  
• Liu, X., Clements, A., Zhao, K., Marmorstein, R. (2006). Structure of the Human Papillomavirus E7 Oncoprotein and Its Mechanism for Inactivation of the Retinoblastoma Tumor Suppressor. J. Biol. Chem. 281: 578-586 [Abstract] [Full Text]  
• Guess, J. C., McCance, D. J. (2005). Decreased Migration of Langerhans Precursor-Like Cells in Response to Human Keratinocytes Expressing Human Papillomavirus Type 16 E6/E7 Is Related to Reduced Macrophage Inflammatory Protein-3{alpha} Production. J. Virol. 79: 14852-14862 [Abstract] [Full Text]  
• Imamura, T., Imamura, C., Iwamoto, Y., Sandell, L. J. (2005). Transcriptional Co-activators CREB-binding Protein/p300 Increase Chondrocyte Cd-rap Gene Expression by Multiple Mechanisms Including Sequestration of the Repressor CCAAT/Enhancer-binding Protein. J. Biol. Chem. 280: 16625-16634 [Abstract] [Full Text]  
• Munger, K., Baldwin, A., Edwards, K. M., Hayakawa, H., Nguyen, C. L., Owens, M., Grace, M., Huh, K. (2004). Mechanisms of Human Papillomavirus-Induced Oncogenesis. J. Virol. 78: 11451-11460 [Full Text]  
• Du, J., Chen, G. G., Vlantis, A. C., Xu, H., Tsang, R. K.Y., van Hasselt, A. C. (2003). The Nuclear Localization of NF{kappa}B and p53 Is Positively Correlated with HPV16 E7 Level in Laryngeal Squamous Cell Carcinoma. J. Histochem. Cytochem. 51: 533-539 [Abstract] [Full Text]