title: Regulatory effects of SKAR in interferon α signaling and its role in the generation of type I IFN responses.
abstract: We provide evidence that S6 kinase 1 (S6K1) Aly/REF-like target (SKAR) is engaged in IFN-α signaling and plays a key role in the generation of IFN responses. Our data demonstrate that IFN-α induces phosphorylation of SKAR, which is mediated by either the p90 ribosomal protein S6 kinase (RSK) or p70 S6 kinase (S6K1), in a cell type-specific manner. This type I IFN-inducible phosphorylation of SKAR results in enhanced interaction with the eukaryotic initiation factor (eIF)4G and recruitment of activated RSK1 to 5' cap mRNA. Our studies also establish that SKAR is present in cap-binding CBP80 immune complexes and that this interaction is mediated by eIF4G. We demonstrate that inducible protein expression of key IFN-α-regulated protein products such as ISG15 and p21(WAF1/CIP1) requires SKAR activity. Importantly, our studies define a requirement for SKAR in the generation of IFN-α-dependent inhibitory effects on malignant hematopoietic progenitors from patients with chronic myeloid leukemia or myeloproliferative neoplasms. Taken altogether, these findings establish critical and essential roles for SKAR in the regulation of mRNA translation of IFN-sensitive genes and induction of IFN-α biological responses.
authors: Robert H. Lurie Comprehensive Cancer Center andDivision of Hematology/Oncology, Northwestern University Medical School, Chicago, IL 60611;
authors: Barbara
authors: B
authors: Kroczynska
authors: Robert H. Lurie Comprehensive Cancer Center andDivision of Hematology/Oncology, Northwestern University Medical School, Chicago, IL 60611;
authors: Swarna
authors: S
authors: Mehrotra
authors: Toronto General Research Institute, University Health Network, andDepartment of Immunology, University of Toronto, Toronto, ON, Canada M5S 2J7;
authors: Beata
authors: B
authors: Majchrzak-Kita
authors: Robert H. Lurie Comprehensive Cancer Center andDivision of Hematology/Oncology, Northwestern University Medical School, Chicago, IL 60611;
authors: Ahmet Dirim
authors: AD
authors: Arslan
authors: Robert H. Lurie Comprehensive Cancer Center andDivision of Hematology/Oncology, Northwestern University Medical School, Chicago, IL 60611;Division of Hematology/Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612;
authors: Jessica K
authors: JK
authors: Altman
authors: Robert H. Lurie Comprehensive Cancer Center andDivision of Hematology/Oncology, Northwestern University Medical School, Chicago, IL 60611;
authors: Brady L
authors: BL
authors: Stein
authors: Robert H. Lurie Comprehensive Cancer Center andDivision of Hematology/Oncology, Northwestern University Medical School, Chicago, IL 60611;
authors: Brandon
authors: B
authors: McMahon
authors: Department of Molecular Biology, Faculty of Biology, University of Warsaw, 02-096, Warsaw, Poland; and.
authors: Piotr
authors: P
authors: Kozlowski
authors: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany.
authors: Philipp J
authors: PJ
authors: Kahle
authors: Robert H. Lurie Comprehensive Cancer Center andDivision of Hematology/Oncology, Northwestern University Medical School, Chicago, IL 60611;Division of Hematology/Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612;
authors: Elizabeth A
authors: EA
authors: Eklund
authors: Toronto General Research Institute, University Health Network, andDepartment of Immunology, University of Toronto, Toronto, ON, Canada M5S 2J7;
authors: Eleanor N
authors: EN
authors: Fish
authors: Robert H. Lurie Comprehensive Cancer Center andDivision of Hematology/Oncology, Northwestern University Medical School, Chicago, IL 60611;Division of Hematology/Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612; l-platanias@northwestern.edu.
authors: Leonidas C
authors: LC
authors: Platanias
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D051379:Mice; D039502:Nuclear Cap-Binding Protein Complex / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; D016898:Interferon-alpha; D039502:Nuclear Cap-Binding Protein Complex; D009687:Nuclear Proteins; C495327:POLDIP3 protein, human; D016601:RNA-Binding Proteins; D014452:Ubiquitins; D006151:Guanosine; C016578:7-methylguanosine; C074034:ISG15 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa