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Start Over Author "Vcelkova, Terezia" Topic interferon-gamma
2 results on '"Vcelkova, Terezia"'

1. Transcriptional Responses to IFN-γ Require Mediator Kinase-Dependent Pause Release and Mechanistically Distinct CDK8 and CDK19 Functions.

Author

Steinparzer I, Sedlyarov V, Rubin JD, Eislmayr K, Galbraith MD, Levandowski CB, Vcelkova T, Sneezum L, Wascher F, Amman F, Kleinova R, Bender H, Andrysik Z, Espinosa JM, Superti-Furga G, Dowell RD, Taatjes DJ, and Kovarik P

Subjects
Animals, Cyclin-Dependent Kinase 8 genetics, Cyclin-Dependent Kinases genetics, Fibroblasts enzymology, Fibroblasts virology, HCT116 Cells, Host-Pathogen Interactions, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphorylation, RNA Polymerase II metabolism, STAT1 Transcription Factor metabolism, Signal Transduction, Vesiculovirus pathogenicity, Cyclin-Dependent Kinase 8 metabolism, Cyclin-Dependent Kinases metabolism, Fibroblasts drug effects, Interferon-gamma pharmacology, Transcription, Genetic drug effects
Abstract

Transcriptional responses to external stimuli remain poorly understood. Using global nuclear run-on followed by sequencing (GRO-seq) and precision nuclear run-on sequencing (PRO-seq), we show that CDK8 kinase activity promotes RNA polymerase II pause release in response to interferon-γ (IFN-γ), a universal cytokine involved in immunity and tumor surveillance. The Mediator kinase module contains CDK8 or CDK19, which are presumed to be functionally redundant. We implemented cortistatin A, chemical genetics, transcriptomics, and other methods to decouple their function while assessing enzymatic versus structural roles. Unexpectedly, CDK8 and CDK19 regulated different gene sets via distinct mechanisms. CDK8-dependent regulation required its kinase activity, whereas CDK19 governed IFN-γ responses through its scaffolding function (i.e., it was kinase independent). Accordingly, CDK8, not CDK19, phosphorylates the STAT1 transcription factor (TF) during IFN-γ stimulation, and CDK8 kinase inhibition blocked activation of JAK-STAT pathway TFs. Cytokines such as IFN-γ rapidly mobilize TFs to "reprogram" cellular transcription; our results implicate CDK8 and CDK19 as essential for this transcriptional reprogramming., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Published
2019
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2. Transcriptional responses to IFN-γ require Mediator kinase-dependent pause release and mechanistically distinct functions of CDK8 and CDK19

Author

Steinparzer, Iris, Sedlyarov, Vitaly, Rubin, Jonathan D., Eislmayr, Kevin, Galbraith, Matthew D., Levandowski, Cecilia B., Vcelkova, Terezia, Sneezum, Lucy, Wascher, Florian, Amman, Fabian, Kleinova, Renata, Bender, Heather, Andrysik, Zdenek, Espinosa, Joaquin M., Superti-Furga, Giulio, Dowell, Robin D., Taatjes, Dylan J., and Kovarik, Pavel

Subjects
Mice, Knockout, Transcription, Genetic, Vesiculovirus, Fibroblasts, Cyclin-Dependent Kinase 8, HCT116 Cells, Article, Cyclin-Dependent Kinases, Mice, Inbred C57BL, Interferon-gamma, Mice, STAT1 Transcription Factor, Host-Pathogen Interactions, Animals, Humans, RNA Polymerase II, Phosphorylation, Signal Transduction
Abstract

Transcriptional responses to external stimuli remain poorly understood. Using global nuclear run-on followed by sequencing (GRO-seq) and precision nuclear run-on sequencing (PRO-seq), we show that CDK8 kinase activity promotes RNA polymerase II pause release in response to interferon-γ (IFN-γ), a universal cytokine involved in immunity and tumor surveillance. The Mediator kinase module contains CDK8 or CDK19, which are presumed to be functionally redundant. We implemented cortistatin A, chemical genetics, transcriptomics, and other methods to decouple their function while assessing enzymatic versus structural roles. Unexpectedly, CDK8 and CDK19 regulated different gene sets via distinct mechanisms. CDK8-dependent regulation required its kinase activity, whereas CDK19 governed IFN-γ responses through its scaffolding function (i.e., it was kinase independent). Accordingly, CDK8, not CDK19, phosphorylates the STAT1 transcription factor (TF) during IFN-γ stimulation, and CDK8 kinase inhibition blocked activation of JAK-STAT pathway TFs. Cytokines such as IFN-γ rapidly mobilize TFs to "reprogram" cellular transcription; our results implicate CDK8 and CDK19 as essential for this transcriptional reprogramming.

Published
2019

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