Host genotype controls the ability of the ISGF3 complex to activate transcription of IFN-inducible genes.
C57BL/6 mice are unable to express the Ifi 202 type genes upon injection in vivo of multiple dsRNA, poly rl:rC, or IFN-treatment in vitro. For this purpose the 5' terminal flanking region (called the b segment of 804 bp) was linked to a heterologous reporter gene chloramphenicol acetyl transferase (CAT) and transfected into NIH3T3 cells or BLK cells derived from the C57BL/6 strain. IFN-alpha induced strong CAT activity in NIH3T3 but not in BLK cells. This lack of transcription activation was not due to a defect in STAT factor activity, since IFN-alpha treatment in the presence of IFN-gamma priming induced translocation of the ISGF3 into the nucleus, and binding to the ISRE (IFN-Stimulated Response Element) of the 202 gene even in C57BL/6 derived cells. Surprisingly when three tandem copies of the 202 ISRE (42 bp) were linked to a heterologous promoter (c-fos promoter) driving the reporter CAT gene, activation was also observed in C57BL/6 cells upon IFN-treatment. Finally, another IFN-inducible gene, namely the Mx, was activated in C57BL/6 mice. Thus, the primary defect of the C57BL/6 strain leading to an impaired Ifi 202 type gene response to IFN appears to be an inability of the ISGF3 complex to activate the endogenous promoter. Altogether these results suggest that unidentified nuclear factors related to the host genotype control the ability of the STAT factors to activate transcription upon IFN-treatment.
Gariglio
M
M
Institute of Microbiology, University of Torino, Italy.
Foresta
P
P
Ying
G G
GG
Gaboli
M
M
Lembo
D
D
Landolfo
S
S
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D017930:Genes, Reporter; D005838:Genotype; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015345:Oligonucleotide Probes; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection
C088830:DENND4A protein, human; D004268:DNA-Binding Proteins; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; C494228:Isgf3g protein, mouse; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D014157:Transcription Factors; D015500:Chloramphenicol O-Acetyltransferase