Critical roles for Rictor/Sin1 complexes in interferon-dependent gene transcription and generation of antiproliferative responses.
We provide evidence that type I IFN-induced STAT activation is diminished in cells with targeted disruption of the Rictor gene, whose protein product is a key element of mTOR complex 2. Our studies show that transient or stable knockdown of Rictor or Sin1 results in defects in activation of elements of the STAT pathway and reduced STAT-DNA binding complexes. This leads to decreased expression of several IFN-inducible genes that mediate important biological functions. Our studies also demonstrate that Rictor and Sin1 play essential roles in the generation of the suppressive effects of IFNα on malignant erythroid precursors from patients with myeloproliferative neoplasms. Altogether, these findings provide evidence for critical functions for Rictor/Sin1 complexes in type I IFN signaling and the generation of type I IFN antineoplastic responses.
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611.
Surinder
S
Kaur
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611.
Barbara
B
Kroczynska
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611.
Bhumika
B
Sharma
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611.
Antonella
A
Sassano
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611.
Ahmet Dirim
AD
Arslan
Toronto Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, Ontario M5S 2J7, Canada.
Beata
B
Majchrzak-Kita
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611.
Brady L
BL
Stein
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611.
Brandon
B
McMahon
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611; Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
Jessica K
JK
Altman
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520.
Bing
B
Su
Department of Biotechnology and Health Sciences, University of Turin, 8 Turin, Italy.
Raffaele A
RA
Calogero
Toronto Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, Ontario M5S 2J7, Canada.
Eleanor N
EN
Fish
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611; Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612. Electronic address: l-platanias@northwestern.edu.
Leonidas C
LC
Platanias
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation; D011087:Polycythemia Vera / Q000378:metabolism / Q000473:pathology; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects*; D048868:Adaptor Proteins, Signal Transducing
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D007370:Interferon Type I; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; C561937:Mapkap1 protein, mouse; D048868:Adaptor Proteins, Signal Transducing
Akt PKB; Antiviral Agents; Cell Signaling; Cytokines/Interferon; Gene Regulation; Interferon; Signal Transduction