Inactivation of interferon regulatory factor-1 tumor suppressor protein byHPV E7 oncoprotein - Implication for the E7-mediated immune evasion mechanism in cervical carcinogenesis

In studying biological roles of interferon regulatory factor (IRF)-1 tumor suppressor in cervical carcinogenesis, we found that HPV E7 is functionally associated with IRF-1. Binding assays indicate a physical interaction betw een IRF-1 and HPV E7 in vivo and in vitro, The carboxyl-terminal transactiv ation domain of IRF-1 was required for the interaction, Transient co-expres sion of E7 significantly inhibits the IRF-1-mediated activation of IFN-P pr omoter in NIH-3T3 cells. Co-transfection of E7 mutants reveals that the pRb -binding portion of E7 is necessary for the E7-mediated inactivation of IRF -1. It was next determined whether histone deacetylase (HDAC) is involved i n the inactivation mechanism as recently suggested, where the carboxyl-term inal zinc finger domain of E7 associates with NURD complex containing HDAC. When trichostatin A, an inhibitor of HDAC, was treated, the repressing act ivity of E7 was released in a dose-dependent manner. Furthermore, the mutat ion of zinc finger abrogates such activity without effect on the interactio n with IRF-1. These results suggest that RPV E7 interferes with the transac tivation function of IRF-1 by recruiting HDAC to the promoter. The immune-p romoting role of IRF-1 evokes the idea that our novel finding might be impo rtant for the elucidation of the E7-mediated immune evading mechanism that is frequently found in cervical cancer.