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Multiple kinases in the interferon-gamma response.


ABSTRACT: Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are essential for responses to interferons (IFNs), most cytokines, and some growth factors. JAK/STAT signaling is not, however, sufficient for a full IFN-gamma response. Here, a convenient, robust, and quantitative flow cytometry-based kinome-wide siRNA screen has identified nine additional kinases as required for the IFN-gamma class II HLA response, seven for an antiviral response, and two for the cytopathic response to encephalomyocarditis virus (EMCV). As one example, inhibition of the IFN-gamma response by siRNA to ataxia telangiectasia-mutated (ATM) differentially affects a spectrum of IFN-gamma-stimulated mRNAs, with inhibitions being seen as early as 1 h after IFN-gamma stimulation. The implication of ATM, with its previously recognized function in chromatin decondensation, in the control of transcription early in the IFN-gamma response highlights both a role for ATM in cytokine responses and a possible correlation with the chromatin decondensation recently observed in response to IFN-gamma in mammalian cells. This work has, therefore, revealed the simplicity, power, and convenience of quantitative flow cytometry-based siRNA screens, a requirement for ATM and multiple additional kinases in the IFN-gamma response and a possible requirement for two of these kinases in the cytopathic response to EMCV.

SUBMITTER: Watling D 

PROVIDER: S-EPMC2329710 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Multiple kinases in the interferon-gamma response.

Watling D D   Carmo C R CR   Kerr I M IM   Costa-Pereira A P AP  

Proceedings of the National Academy of Sciences of the United States of America 20080415 16


Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are essential for responses to interferons (IFNs), most cytokines, and some growth factors. JAK/STAT signaling is not, however, sufficient for a full IFN-gamma response. Here, a convenient, robust, and quantitative flow cytometry-based kinome-wide siRNA screen has identified nine additional kinases as required for the IFN-gamma class II HLA response, seven for an antiviral response, and two for the cytopathic res  ...[more]

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