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CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance.

ABSTRACT: 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.

SUBMITTER: Putz EM

PROVIDER: S-EPMC3748339 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance.

Putz Eva Maria EM Putz Eva Maria EM Gotthardt Dagmar D Hoermann Gregor G Csiszar Agnes A Wirth Silvia S Berger Angelika A Straka Elisabeth E Rigler Doris D Wallner Barbara B Jamieson Amanda M AM Pickl Winfried F WF Zebedin-Brandl Eva Maria EM Müller Mathias M Decker Thomas T Sexl Veronika V

Cell reports 20130808 3

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 ...[more]

PMID: 23933255

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