Cell Reports
(Aug 2013)
CDK8-Mediated STAT1-S727 Phosphorylation Restrains NK Cell Cytotoxicity and Tumor Surveillance
Eva Maria Putz,
Dagmar Gotthardt,
Gregor Hoermann,
Agnes Csiszar,
Silvia Wirth,
Angelika Berger,
Elisabeth Straka,
Doris Rigler,
Barbara Wallner,
Amanda M. Jamieson,
Winfried F. Pickl,
Eva Maria Zebedin-Brandl,
Mathias Müller,
Thomas Decker,
Veronika Sexl
Affiliations
Eva Maria Putz
Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Dagmar Gotthardt
Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Gregor Hoermann
Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
Agnes Csiszar
Research Institute of Molecular Pathology, 1030 Vienna, Austria
Silvia Wirth
Research Institute of Molecular Pathology, 1030 Vienna, Austria
Angelika Berger
Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Elisabeth Straka
Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Doris Rigler
Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Barbara Wallner
Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Amanda M. Jamieson
Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria
Winfried F. Pickl
Institute of Immunology, Medical University of Vienna, 1090 Vienna, Austria
Eva Maria Zebedin-Brandl
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria
Mathias Müller
Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Thomas Decker
Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria
Veronika Sexl
Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
DOI
https://doi.org/10.1016/j.celrep.2013.07.012
Journal volume & issue
Vol. 4,
no. 3
Abstract
Read online
The transcription factor STAT1 is important in natural killer (NK) cells, which provide immediate defense against tumor and virally infected cells. We show that mutation of a single phosphorylation site (Stat1-S727A) enhances NK cell cytotoxicity against a range of tumor cells, accompanied by increased expression of perforin and granzyme B. Stat1-S727A mice display significantly delayed disease onset in NK cell-surveilled tumor models including melanoma, leukemia, and metastasizing breast cancer. Constitutive phosphorylation of S727 depends on cyclin-dependent kinase 8 (CDK8). Inhibition of CDK8-mediated STAT1-S727 phosphorylation may thus represent a therapeutic strategy for stimulating NK cell-mediated tumor surveillance.
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