PMID- 12163591 OWN - NLM STAT- MEDLINE DCOM- 20020906 LR - 20220410 IS - 0022-538X (Print) IS - 1098-5514 (Electronic) IS - 0022-538X (Linking) VI - 76 IP - 17 DP - 2002 Sep TI - 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. PG - 8710-21 AB - 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-kappaB (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-kappaB/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-kappaB/p65 binding site. This inhibition appears to result from the ability of HPV-16 E6 to compete with NF-kappaB/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-kappaB/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. FAU - Huang, Shih-Min AU - Huang SM AD - Department of Microbiology and Immunology. The Cancer Center, University of Rochester, Rochester, New York 14642, USA. FAU - McCance, D J AU - McCance DJ LA - eng GR - R01 DE013526/DE/NIDCR NIH HHS/United States GR - DE13526/DE/NIDCR NIH HHS/United States GR - P01 AI-99-008/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Cell Cycle Proteins) RN - 0 (E6 protein, Human papillomavirus type 16) RN - 0 (Interleukin-8) RN - 0 (NF-kappa B) RN - 0 (Nuclear Proteins) RN - 0 (Oncogene Proteins, Viral) RN - 0 (Papillomavirus E7 Proteins) RN - 0 (Repressor Proteins) RN - 0 (Trans-Activators) RN - 0 (Transcription Factors) RN - 0 (oncogene protein E7, Human papillomavirus type 16) RN - EC 2.3.1.- (Acetyltransferases) RN - EC 2.3.1.48 (Histone Acetyltransferases) RN - EC 2.3.1.48 (NCOA1 protein, human) RN - EC 2.3.1.48 (Nuclear Receptor Coactivator 1) RN - EC 2.3.1.48 (p300-CBP Transcription Factors) RN - EC 2.3.1.48 (p300-CBP-associated factor) SB - IM MH - Acetyltransferases/genetics/metabolism MH - Binding Sites MH - Binding, Competitive MH - Cell Cycle Proteins/genetics/metabolism MH - Cells, Cultured MH - *Down-Regulation MH - Histone Acetyltransferases MH - Humans MH - Interleukin-8/genetics/*metabolism MH - Keratinocytes MH - Mutation MH - NF-kappa B/metabolism MH - Nuclear Proteins/genetics/metabolism MH - Nuclear Receptor Coactivator 1 MH - Oncogene Proteins, Viral/genetics/*metabolism MH - Papillomavirus E7 Proteins MH - Promoter Regions, Genetic/*genetics MH - *Repressor Proteins MH - Trans-Activators/genetics/metabolism MH - Transcription Factors/genetics/metabolism MH - p300-CBP Transcription Factors PMC - PMC136974 EDAT- 2002/08/07 10:00 MHDA- 2002/09/07 10:01 PMCR- 2002/09/01 CRDT- 2002/08/07 10:00 PHST- 2002/08/07 10:00 [pubmed] PHST- 2002/09/07 10:01 [medline] PHST- 2002/08/07 10:00 [entrez] PHST- 2002/09/01 00:00 [pmc-release] AID - 0426 [pii] AID - 10.1128/jvi.76.17.8710-8721.2002 [doi] PST - ppublish SO - J Virol. 2002 Sep;76(17):8710-21. doi: 10.1128/jvi.76.17.8710-8721.2002.