IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage
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HyeonJoo Cheon [1] ; Elise G Holvey-Bates [1] ; John W Schoggins [2] ; Samuel Forster [3] ; Paul Hertzog [3] ; Naoko Imanaka [2] ; Charles M Rice [2] ; Mark W Jackson [4] ; Damian J Junk [4] ; George R Stark [1]
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[1] Cleveland Clinic
Cleveland Clinic
City of Cleveland, Estados Unidos
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[2] Rockefeller University
Rockefeller University
Estados Unidos
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[3] Monash Institute of Medical Research
Monash Institute of Medical Research
Australia
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[4] Case Western Reserve University
Case Western Reserve University
City of Cleveland, Estados Unidos
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- Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 32, Nº. 20, 2013, págs. 2751-2763
- Idioma: inglés
- Enlaces
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Resumen
A single high dose of interferon-β (IFNβ) activates powerful cellular responses, in which many anti-viral, pro-apoptotic, and anti-proliferative proteins are highly expressed. Since some of these proteins are deleterious, cells downregulate this initial response rapidly. However, the expression of many anti-viral proteins that do no harm is sustained, prolonging a substantial part of the initial anti-viral response for days and also providing resistance to DNA damage. While the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase, the related factor un-phosphorylated ISGF3 (U-ISGF3), formed by IFNβ-induced high levels of IRF9 and STATs 1 and 2 without tyrosine phosphorylation, drives the second prolonged response. The U-ISGF3-induced anti-viral genes that show prolonged expression are driven by distinct IFN stimulated response elements (ISREs). Continuous exposure of cells to a low level of IFNβ, often seen in cancers, leads to steady-state increased expression of only the U-ISGF3-dependent proteins, with no sustained increase in other IFNβ-induced proteins, and to constitutive resistance to DNA damage.
