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CDK8 Kinase Phosphorylates Transcription Factor STAT1 to Selectively Regulate the Interferon Response
Open accessAbstract
Gene regulation by cytokine-activated transcription factors of the signal transducer and activator of transcription (STAT) family requires serine phosphorylation within the transactivation domain (TAD). STAT1 and STAT3 TAD phosphorylation occurs upon promoter binding by an unknown kinase. Here, we show that the cyclin-dependent kinase 8 (CDK8) module of the Mediator complex phosphorylated regulatory sites within the TADs of STAT1, STAT3, and STAT5, including S727 within the STAT1 TAD in the interferon (IFN) signaling pathway. We also observed a CDK8 requirement for IFN-γ-inducible antiviral responses. Microarray analyses revealed that CDK8-mediated STAT1 phosphorylation positively or negatively regulated over 40% of IFN-γ-responsive genes, and RNA polymerase II occupancy correlated with gene expression changes. This divergent regulation occurred despite similar CDK8 occupancy at both S727 phosphorylation-dependent and -independent genes. These data identify CDK8 as a key regulator of STAT1 and antiviral responses and suggest a general role for CDK8 in STAT-mediated transcription. As such, CDK8 represents a promising target for therapeutic manipulation of cytokine responses.
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“In macrophages, CDK8 appears to be the main kinase driving STAT1 serine phosphorylation in response to IFN gamma stimulation”
From CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci (2020) · cites this paper as Bancerek et al., 2013
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“Previous studies have described CDKs as regulators of STAT1 Ser phosphorylation in different systems”
From CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci (2020) · cites this paper as Bancerek et al., 2013
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Metadata
- Authors
- Bancerek, J., Poss, Z. C., Steinparzer, I., Sedlyarov, V., Pfaffenwimmer, T., Mikulic, I., Dölken, L., Strobl, B., Müller, M., Taatjes, D. J., & Kovarik, P.
- Affiliations
- University of Vienna (AT)
- University of Colorado Boulder (US)
- University of Cambridge (GB)
- University of Veterinary Medicine Vienna (AT)
- Corresponding author
- Kovarik, Pavel
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 38
- Issue
- 2
- Pages
- 250-262
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC3580287
- OpenAlex
- W2059553622
- Cited by
- 297
- References
- 53
- Citations by year
- 2026: 32 · 2025: 28 · 2024: 29 · 2023: 21 · 2022: 23 · 2021: 20 · 2020: 24 · 2019: 27 · 2018: 19 · 2017: 24 · 2016: 15 · 2015: 13 · 2014: 13 · 2013: 9
- FWCI
- 8.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Immunity (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Austrian Science Fund
- Universität Wien
- National Institutes of Health
- National Cancer Institute (R01CA127364, P30CA046934)
- National Institute of General Medical Sciences (T32-GM08759, T32GM008759, T32GM142607)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- CDK8, STAT1, STAT3, STAT5, serine phosphorylation, transactivation domain, Mediator complex, interferon signaling, interferon-gamma, antiviral response, RNA polymerase II occupancy, gene expression regulation
- MeSH terms
- Animals, Fibroblasts, Gene Expression Regulation, Humans, Interferon-gamma, Phosphorylation, Promoter Regions, Genetic, RNA Polymerase II, Transcription, Genetic, Signal Transduction, Interleukin-6, Vesiculovirus, Oligonucleotide Array Sequence Analysis, STAT1 Transcription Factor, STAT3 Transcription Factor, STAT5 Transcription Factor, Mice, Cyclin-Dependent Kinase 8, Hep G2 Cells
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