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- Agnieszka Witalisz-Siepracka
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
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- Dagmar Gotthardt
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
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- Michaela Prchal-Murphy
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
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- Zrinka Didara
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
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- Ingeborg Menzl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
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- Daniela Prinz
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
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- Leo Edlinger
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
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- Eva Maria Putz
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
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- Veronika Sexl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
説明
<jats:title>Abstract</jats:title><jats:p>Cyclin-dependent kinase 8 (CDK8) is a member of the transcription-regulating CDK family. CDK8 activates or represses transcription by associating with the mediator complex or by regulating transcription factors. Oncogenic activity of CDK8 has been demonstrated in several cancer types. Targeting CDK8 represents a potential therapeutic strategy. Because knockdown of CDK8 in a natural killer (NK) cell line enhances cytotoxicity and NK cells provide the first line of immune defense against transformed cells, we asked whether inhibiting CDK8 would improve NK-cell antitumor responses. In this study, we investigated the role of CDK8 in NK-cell function in vivo using mice with conditional ablation of CDK8 in NKp46+ cells (Cdk8fl/flNcr1Cre). Regardless of CDK8 expression, NK cells develop and mature normally in bone marrow and spleen. However, CDK8 deletion increased expression of the lytic molecule perforin, which correlated with enhanced NK-cell cytotoxicity in vitro. This translates into improved NK cell–mediated tumor surveillance in vivo in three independent models: B16F10 melanoma, v-abl+ lymphoma, and a slowly developing oncogene-driven leukemia. Our results thereby define a suppressive effect of CDK8 on NK-cell activity. Therapies that target CDK8 in cancer patients may enhance NK-cell responses against tumor cells. Cancer Immunol Res; 6(4); 458–66. ©2018 AACR.</jats:p>
収録刊行物
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- Cancer Immunology Research
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Cancer Immunology Research 6 (4), 458-466, 2018-04-01
American Association for Cancer Research (AACR)
