Cells resistant to interferon-beta respond to interferon-gamma via the Stat1-IRF-1 pathway.
The mechanism responsible for the induction of the 2-5A synthetase gene by Interferon-gamma (IFN-gamma) (type II) was studied in Friend leukemia cells. It was previously shown that activation of 2-5A synthetase gene expression by IFN-gamma in the 3Cl8 cell, a clone resistant to IFN-alpha,beta (type I), correlates with the formation of two major complexes, designated Fg and Fc, that bind to the interferon-stimulated responsive element of the gene. Conversely, in a clone resistant to both types of IFNs (3 gamma R8), no induction of DNA-protein complexes or of 2-5A synthetase gene expression was detected. In the present report the Fg complex has been characterized as including the interferon regulatory factor 1 (IRF-1), whereas the Fc factor, present also in control cells, has been characterized as composed of IRF-2. Incubation of cell extracts with antibodies to IRF-1 abolishes the formation of the Fg complex, and antibodies to IRF-2 abolish the formation of the Fc complex. Moreover, in the 3Cl8 cell, IFN-gamma is able to induce in few minutes the formation of a complex between a DNA element identified as the IFN-gamma activation site (GAS), present on the IRF-1 gene promoter, and the STAT1 protein. These findings suggest that in cells resistant to type I IFN, IFN-gamma is able, through the activation of the STAT1 protein, to induce the expression of the IRF-1 factor which in turn seems to be sufficient to transactivate the 2-5A synthetase gene.
Coccia
E M
EM
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
Marziali
G
G
Stellacci
E
E
Perrotti
E
E
Ilari
R
R
Orsatti
R
R
Battistini
A
A
D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002999:Clone Cells; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004351:Drug Resistance; D004790:Enzyme Induction / Q000187:drug effects / Q000276:immunology; D005622:Friend murine leukemia virus; D050856:Interferon Regulatory Factor-1; D016899:Interferon-beta / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D007942:Leukemia, Experimental / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D013379:Substrate Specificity; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016899:Interferon-beta; D007371:Interferon-gamma; D015088:2',5'-Oligoadenylate Synthetase