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- W52531865 abstract "A single high dose of IFNβ activates powerful cellular responses in which many antiviral, pro-apoptotic, and anti-proliferative proteins are highly expressed. The expression of IFN-stimulated genes (ISGs) is mediated by ISGF3, consisting of IRF9 and tyrosine phosphorylated STATs 1 and 2. This initial response to IFNβ is rapid and transient, so that the expression of most ISGs returns to basal levels within a day. However, the expression of some ISGs is prolonged for many days. We found that high levels of STAT1, STAT2, and IRF9 proteins that lack tyrosine phosphorylation are critical for the prolonged second phase response to IFNβ. The expression of the STAT1, STAT2, and IRF9 proteins is increased by IFNβ at late times (>24 h), and these proteins form a complex resembling ISGF3 (named unphosphorylated ISGF3, U-ISGF3), and bind to ISREs of target genes independently of tyrosine phosphorylation of STATs 1 and 2. U-ISGF3 induces only a subset of ISGs (20–30% of the total), which are mostly known to be antiviral genes and are also highly expressed in therapy-resistant cancer cells, but not cytotoxic ISGs. We observed that, in the absence of interferon treatment, high levels of U-ISGF3 significantly reduced the replication of many RNA viruses. High U-ISGF3 levels are correlated with resistance of cancer cells to DNA damage induced by radiation, etoposide, or doxorubicin. Knocking STAT1 and IRF9 down to decrease U-ISGF3 levels sensitized cancer cells to doxorubicin-induced DNA damage. Continuous exposure of cells to a low level of IFNβ, often seen in cancers, leads to steady-state increases in the expression of only the U-ISGF3-dependent genes, with no sustained increases of IFNβ-induced cytotoxic genes. Our study has elucidated that the U-ISGF3-dependent response to IFNβ prolongs the antiviral effects, but leads to DNA damage resistance, which inhibits responses to cancer therapy." @default.
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- W52531865 date "2013-09-01" @default.
- W52531865 modified "2023-09-24" @default.
- W52531865 title "44" @default.
- W52531865 doi "https://doi.org/10.1016/j.cyto.2013.06.047" @default.
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