title: Regulatory effects of ribosomal S6 kinase 1 (RSK1) in IFNλ signaling.
abstract: Although the mechanisms of generation of signals that control transcriptional activation of Type III IFN (IFNλ)-regulated genes have been identified, very little is known about the mechanisms by which the IFNλ receptor generates signals for mRNA translation of IFNλ-activated genes. We provide evidence that IFNλ activates the p90 ribosomal protein S6 kinase 1 (RSK1) and its downstream effector, initiation factor eIF4B. Prior to its engagement by the IFNλ receptor, the non-active form of RSK1 is present in a complex with the translational repressor 4E-BP1 in IFNλ-sensitive cells. IFNλ-inducible phosphorylation/activation of RSK1 results in its dissociation from 4E-BP1 at the same time that 4E-BP1 dissociates from eIF4E to allow formation of eIF4F and initiation of cap-dependent translation. Our studies demonstrate that such IFNλ-dependent engagement of RSK1 is essential for up-regulation of p21(WAF1/CIP1) expression, suggesting a mechanism for generation of growth-inhibitory responses. Altogether, our data provide evidence for a critical role for the activated RSK1 in IFNλ signaling.
authors.affiliation: Division of Hematology-Oncology, Robert H Lurie Comprehensive Cancer Center, Northwestern University Medical School and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60611, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kroczynska
authors.forename: Sonali
authors.initials: S
authors.lastname: Joshi
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eklund
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Kotenko
authors.forename: Eleanor N
authors.initials: EN
authors.lastname: Fish
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D014176:Protein Biosynthesis / Q000502:physiology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000095022:Interferon Lambda
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D048049:Extracellular Signal-Regulated MAP Kinases; D006151:Guanosine; D007372:Interferons; D007378:Interleukins; D010750:Phosphoproteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases; C116616:8-methylguanosine; C493956:CDKN1A protein, human; C087000:EIF4EBP1 protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C546842:MTOR protein, human; C069329:RPS6KA1 protein, human