2007
DOI: 10.1074/jbc.m607365200
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Regulatory Effects of Mammalian Target of Rapamycin-activated Pathways in Type I and II Interferon Signaling

Abstract: The mechanisms regulating initiation of mRNA translation for the generation of protein products that mediate interferon (IFN) responses are largely unknown. We have previously shown that both Type I and II IFNs engage the mammalian target of rapamycin (mTOR), resulting in downstream phosphorylation and deactivation of the translational repressor 4E-BP1 (eIF4E-binding protein 1). In the current study, we provide direct evidence that such regulation of 4E-BP1 by IFN␣ or IFN␥ results in sequential dissociation of… Show more

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Cited by 107 publications
(140 citation statements)
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“…Initially, we examined the effects of targeted disruption of the Mnk1 and/or Mnk2 genes on ISG15 expression. ISG15 is an IFN-inducible protein, whose expression is enhanced in 4E-BP1 knockout cells (11) and is known to play important roles in the generation of IFN-dependent biological responses via regulation of ISG15 conjugation to cellular proteins (ISGylation) (23,24). Mnk1, Mnk2, and double Mnk1/Mnk2 knockout MEFs were treated with mouse IFN␣, and the expression of ISG15 protein was compared with parental wild-type MEFs.…”
Section: Resultsmentioning
confidence: 99%
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“…Initially, we examined the effects of targeted disruption of the Mnk1 and/or Mnk2 genes on ISG15 expression. ISG15 is an IFN-inducible protein, whose expression is enhanced in 4E-BP1 knockout cells (11) and is known to play important roles in the generation of IFN-dependent biological responses via regulation of ISG15 conjugation to cellular proteins (ISGylation) (23,24). Mnk1, Mnk2, and double Mnk1/Mnk2 knockout MEFs were treated with mouse IFN␣, and the expression of ISG15 protein was compared with parental wild-type MEFs.…”
Section: Resultsmentioning
confidence: 99%
“…We have also established the relevance of this pathway in the generation of IFN-antiviral responses and identified Tsc2 and 4E-BP1 as key and essential elements in the control of generation of the biological effects of IFNs (11). Work from others has also implicated mTOR in the regulation of IFN-induced apoptosis (10), while in recent studies using cells with targeted deletion of both the Akt1 and Akt2 genes, we established Akt as a critical element of the IFN-signaling pathway required for engagement of mTOR and for mRNA translation of IFN-regulated genes (12,25).…”
Section: Discussionmentioning
confidence: 98%
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“…In fact, as aberrant cap-dependent translation has been implicated in the pathogenesis of certain malignancies, there are ongoing efforts to develop clinical-translational therapeutic approaches targeting mTOR for the treatment of cancer (40)(41)(42). However, there is also recent evidence that, under certain circumstances, the mTOR pathway can be activated by growth inhibitory cytokines such as interferons (15), to mediate diverse responses such as antiviral activities (15), and even pro-apoptotic effects (43). Our finding that ATRA-and cisRA-inducible upregulation of p21 Waf1/Cip1 protein-expression is regulated by mTORmediated inhibition of 4E-BP1 activity, provides direct evidence that this pathway can be utilized by different ligands, to generate diverse biological responses.…”
Section: Discussionmentioning
confidence: 99%
“…Cells were incubated with ATRA or 13-cis-RA for the indicated times and lysed in phosphorylation lysis buffer (15,16). In experiments in which the effects of rapamycin were examined, rapamycin (20 nM) was added for 2.5 hours prior to cell lysis (8).…”
Section: Immunoprecipitations and Immunoblottingmentioning
confidence: 99%