title: Central role of ULK1 in type I interferon signaling.
abstract: We provide evidence that the Unc-51-like kinase 1 (ULK1) is activated during engagement of the type I interferon (IFN) receptor (IFNR). Our studies demonstrate that the function of ULK1 is required for gene transcription mediated via IFN-stimulated response elements (ISRE) and IFNγ activation site (GAS) elements and controls expression of key IFN-stimulated genes (ISGs). We identify ULK1 as an upstream regulator of p38α mitogen-activated protein kinase (MAPK) and establish that the regulatory effects of ULK1 on ISG expression are mediated possibly by engagement of the p38 MAPK pathway. Importantly, we demonstrate that ULK1 is essential for antiproliferative responses and type I IFN-induced antineoplastic effects against malignant erythroid precursors from patients with myeloproliferative neoplasms. Together, these data reveal a role for ULK1 as a key mediator of type I IFNR-generated signals that control gene transcription and induction of antineoplastic responses.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Saleiro
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Swarna
authors.initials: S
authors.lastname: Mehrotra
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kroczynska
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
authors.forename: Elspeth M
authors.initials: EM
authors.lastname: Beauchamp
authors.affiliation: Department of Molecular Biology, Institute of Genetics and Animal Breeding, 05-552 Jastrzebiec n/Warsaw, Poland; iPS Cell-Based Disease Modeling Group, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, 13092 Berlin, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Lisowski
authors.affiliation: Toronto General Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, ON M5G 2M1, Canada.
authors.forename: Beata
authors.initials: B
authors.lastname: Majchrzak-Kita
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Tushar D
authors.initials: TD
authors.lastname: Bhagat
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Brady L
authors.initials: BL
authors.lastname: Stein
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: McMahon
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Altman
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Ewa M
authors.initials: EM
authors.lastname: Kosciuczuk
authors.affiliation: Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Chunfa
authors.initials: C
authors.lastname: Jie
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Nadereh
authors.initials: N
authors.lastname: Jafari
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.affiliation: Human Oncology and Pathogenesis Program, and Leukemia Service, Memorial Sloan Kettering Cancer Center; and Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Toronto General Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, ON M5G 2M1, Canada.
authors.forename: Eleanor N
authors.initials: EN
authors.lastname: Fish
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Verma
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA. Electronic address: l-platanias@northwestern.edu.
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D000071189:Autophagy-Related Protein-1 Homolog; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D041905:Erythroid Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009196:Myeloproliferative Disorders / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; D048051:p38 Mitogen-Activated Protein Kinases