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CDK8 Fine-Tunes IL-6 Transcriptional ...
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Document type :
Article dans une revue scientifique
DOI :
10.1016/j.celrep.2020.108545
PMID :
33357429
Title :
CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci
Author(s) :
Martinez-Fabregas, Jonathan [Auteur]
University of Dundee
Wang, Luopin [Auteur]
Purdue University [West Lafayette]
Pohler, Elizabeth [Auteur]
University of Dundee
Cozzani, Adeline [Auteur]
Institut pour la recherche sur le cancer de Lille [Lille] [IRCL]
Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Wilmes, Stephan [Auteur]
University of Dundee
Kazemian, Majid [Auteur correspondant]
Purdue University [West Lafayette]
Mitra, Suman [Auteur correspondant]
Institut pour la recherche sur le cancer de Lille [Lille] [IRCL]
Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Moraga, Ignacio [Auteur correspondant]
University of Dundee
Journal title :
Cell Reports
Pages :
108545 -
Publisher :
Elsevier Inc
Publication date :
2020-12-22
ISSN :
2211-1247
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
Cytokines are highly pleiotropic ligands that regulate the immune response. Here, using interleukin-6 (IL-6) as a model system, we perform detailed phosphoproteomic and transcriptomic studies in human CD4+ T helper 1 (Th-1) ...
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Cytokines are highly pleiotropic ligands that regulate the immune response. Here, using interleukin-6 (IL-6) as a model system, we perform detailed phosphoproteomic and transcriptomic studies in human CD4+ T helper 1 (Th-1) cells to address the molecular bases defining cytokine functional pleiotropy. We identify CDK8 as a negative regulator of STAT3 transcriptional activities, which interacts with STAT3 upon IL-6 stimulation. Inhibition of CDK8 activity, using specific small molecule inhibitors, reduces the IL-6-induced phosphoproteome by 23% in Th-1 cells, including STAT3 S727 phosphorylation. STAT3 binding to target DNA sites in the genome is increased upon CDK8 inhibition, which results in a concomitant increase in STAT3-mediated transcriptional activity. Importantly, inhibition of CDK8 activity under Th-17 polarizing conditions results in an enhancement of Th-17 differentiation. Our results support a model where CDK8 regulates STAT3 transcriptional processivity by modulation of its gene loci resident time, critically contributing to diversification of IL-6 responses.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
Non
Collections :
  • Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277
Source :
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