VIRAL INDUCTION OF THE HUMAN BETA-INTERFERON PROMOTER - MODULATION OF TRANSCRIPTION BY NF-KAPPA-B/REL PROTEINS AND INTERFERON REGULATORY FACTORS

被引:86
作者
GAROUFALIS, E
KWAN, I
LIN, RT
MUSTAFA, A
PEPIN, N
ROULSTON, A
LACOSTE, J
HISCOTT, J
机构
[1] SIR MORTIMER B DAVIS JEWISH HOSP,LADY DAVIS INST MED RES,TERRY FOX MOLEC ONCOL GRP,MONTREAL H3T 1E2,PQ,CANADA
[2] MCGILL UNIV,DEPT MICROBIOL & IMMUNOL,MONTREAL H3T 1E2,PQ,CANADA
关键词
D O I
10.1128/JVI.68.8.4707-4715.1994
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Multiple regulatory domains within the -100 region of the beta interferon (IFN-beta) promoter control the inducible response of the IFN gene to virus infection. In this study, we demonstrate that the formation of NF-kappa B specific complexes on the positive regulatory domain II (PRDII) precedes the onset of detectable IFN-beta transcription in Sendai virus-infected cells. By using NF-kappa B subunit-specific antibodies, a temporal shift in the composition of NF-kappa B subunits in association with the PRDII domain is detected as a function of time after virus infection. Furthermore, a virus-induced degradation of I kappa B alpha (MAD3) protein is observed between 2 and 8 h after infection; at later times, de novo synthesis of I kappa B alpha restores I kappa B alpha to levels found in uninduced cells and correlates with the down regulation of IFN-beta transcription. In cotransfection experiments using various NF-kappa B subunit expression plasmids and two copies of PRDII/NF-kappa B linked to a chloramphenicol acetyltransferase reporter gene, we demonstrate that expression of p65, c-Rel, or p50 or combinations of p50-p65 and p65-c-Rel differentially stimulated PRDII-dependent transcription. Coexpression of I kappa B alpha completely abrogated p65-, c-Rel-, or p65-p50-induced gene activity. When the entire IFN-beta promoter (-281 to f19) was used in coexpression studies, synergistic stimulation of IFN-beta promoter activity was obtained when NF-kappa B subunits were coexpressed together with the IFN regulatory factor 1 (IRF-1) transcription factor. Overexpression of either I kappa B or the IRF-2 repressor was able to abrogate inducibility of the IFN-beta promoter. Thus, multiple regulatory events-including differential activation of DNA-binding NF-kappa B heterodimers, degradation of I kappa B alpha, synergistic interaction between IRF-1 and NF-kappa B, and decreased repression by I kappa B and IRF-2-are all required for the transcriptional activation of the IFN-beta promoter.
引用
收藏
页码:4707 / 4715
页数:9
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