MilliporeSigma
  • CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci.

CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci.

Cell reports (2020-12-29)
Jonathan Martinez-Fabregas, Luopin Wang, Elizabeth Pohler, Adeline Cozzani, Stephan Wilmes, Majid Kazemian, Suman Mitra, Ignacio Moraga
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Roscovitine, A potent, reversible, and selective inhibitor of Cdks that exhibits about 10-fold greater efficacy towards p34-cdk1 and p33-cdk2 and 20-fold greater efficacy towards p33-cdk5 relative to Olomoucine.
Sigma-Aldrich
Cdk9 Inhibitor II, The Cdk9 Inhibitor II, also referenced under CAS 140651-18-9, controls the biological activity of Cdk9. This small molecule/inhibitor is primarily used for Phosphorylation & Dephosphorylation applications.
Sigma-Aldrich
Ionomycin calcium salt from Streptomyces conglobatus, powder, ≥98% (HPLC)
Sigma-Aldrich
Brefeldin A, from Penicillium brefeldianum, ≥99% (HPLC and TLC)
Sigma-Aldrich
DL-Dithiothreitol, ≥98% (HPLC), ≥99.0% (titration)
Sigma-Aldrich
Iodoacetamide, ≥99% (NMR), crystalline
Sigma-Aldrich
PP2, ≥98% (HPLC)
Sigma-Aldrich
Indole-3-acetic acid sodium salt, suitable for plant cell culture, BioReagent, ≥98%
Sigma-Aldrich
L-Arginine, from non-animal source, meets EP, USP testing specifications, suitable for cell culture, 98.5-101.0%
Sigma-Aldrich
Phorbol 12-myristate 13-acetate, ≥99% (TLC), film or powder
Sigma-Aldrich
L-Lysine monohydrochloride, from non-animal source, meets EP, JP, USP testing specifications, suitable for cell culture, 98.5-101.0%
Magnetic Stir Bar, for use with For 3.0-5.0mL vessels, pkg of 6 ea, PTFE
Sigma-Aldrich
Duolink® In Situ Detection Reagents Red