Journal
EMBO JOURNAL
Volume 32, Issue 20, Pages 2751-2763Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/emboj.2013.203
Keywords
anti-viral genes; DNA damage resistance; interferon-beta; unphosphorylated interferon-stimulated gene factor 3 (U-ISGF3)
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Funding
- National Institutes of Health [PO1 CA062220, RO1 AI091707, K01 DK095031]
- Greenberg Medical Research Institute
- Starr Foundation
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A single high dose of interferon-beta (IFN beta) 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 down-regulate 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 IFN beta-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 IFN beta, often seen in cancers, leads to steady-state increased expression of only the U-ISGF3-dependent proteins, with no sustained increase in other IFN beta-induced proteins, and to constitutive resistance to DNA damage.
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