Abrogation of IRF-1 response by high-risk HPV E7 protein in vivo.
We have previously reported that human papillomavirus (HPV) E7 interacts with IRF-1, a key regulator of cellular immune response, and abrogates its transactivation function at the molecular level in vitro. To confirm our previous data, we investigated in vivo the E7-mediated down-regulation of IRF-1 using HPV E7-inducible cells and transgenic mice expressing HPV-18 E6/E7. When E7 was induced in the absence of tetracycline, the expression of target genes of IRF-1 (TAP-1, IFN-beta, MCP-1 that are important for cellular immunity) was clearly reduced as determined by RT-PCR. In addition, the IRF-1 activity was down-regulated in E7-expressing cells into which IFN-beta-CAT reporter plasmid was transfected. To further investigate the E7-mediated immune regulation in vivo, we constructed transgenic mice expressing E6 and E7 genes of HPV-18 under the control of HPV-18 promoter (URR). From several rounds of breeding, we obtained from a transgenic line that developed a cervical dysplasia and expressed E6/E7 as determined by histological examination and RT-PCR, respectively. Subsequent RT-PCR analysis indicated that TAP-1, IFN-beta, and MCP-1 genes were less expressed in a cervical tissue derived from transgenic mouse, when compared with a cervix derived from normal mouse. From these results, we conclude that the E7 transgene expression inactivates the transactivation function of IRF-1 in vivo, which might be important for the elucidation of the E7-mediated immune evading mechanism that is frequently found in cervical cancer.
Um
Soo-Jong
SJ
Department of Bioscience and Biotechnology/Institute of Bioscience, Sejong University, Seoul, South Korea
Rhyu
Jae-Woong
JW
Kim
Eun-Joo
EJ
Jeon
Kook-Che
KC
Hwang
Eun-Seoung
ES
Park
Jong-Sup
JS
D016475:3T3 Cells; D000818:Animals; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D050856:Interferon Regulatory Factor-1; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D009856:Oncogene Proteins, Viral; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D016899:Interferon-beta; D015500:Chloramphenicol O-Acetyltransferase