Inactivation of interferon regulatory factor-1 tumor suppressor protein by HPV 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 between IRF-1 and HPV E7 in vivo and in vitro. The carboxyl-terminal transactivation domain of IRF-1 was required for the interaction. Transient co-expression of E7 significantly inhibits the IRF-1-mediated activation of IFN-beta promoter 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 in the inactivation mechanism as recently suggested, where the carboxyl-terminal zinc finger domain of E7 associates with NURD complex containing HDAC. When trichostatin A, an inhibitor of HDAC, was treated, the repressing activity of E7 was released in a dose-dependent manner. Furthermore, the mutation of zinc finger abrogates such activity without effect on the interaction with IRF-1. These results suggest that HPV E7 interferes with the transactivation function of IRF-1 by recruiting HDAC to the promoter. The immune-promoting role of IRF-1 evokes the idea that our novel finding might be important for the elucidation of the E7-mediated immune evading mechanism that is frequently found in cervical cancer.
Park
J S
JS
Department of Obstetrics and Gynecology, Catholic University Medical College, Seoul, 137-040 Korea.
Kim
E J
EJ
Kwon
H J
HJ
Hwang
E S
ES
Namkoong
S E
SE
Um
S J
SJ
D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D006801:Humans; D050856:Interferon Regulatory Factor-1; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D050725:Papillomavirus E7 Proteins; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D015533:Transcriptional Activation; D002583:Uterine Cervical Neoplasms / Q000209:etiology* / Q000276:immunology
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010750:Phosphoproteins; D016160:Retinoblastoma Protein; C059731:oncogene protein E7, Human papillomavirus type 16