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Transcriptional responses to interferon require Mediator kinase-dependent pause release and mechanistically distinct functions of CDK8 and CDK19

ABSTRACT: Transcriptional responses to interferon require Mediator kinase-dependent pause release and mechanistically distinct functions of CDK8 and CDK19

PROVIDER: PRJNA531516 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8867630.fastq.gz	Fastqsanger.gz
	SRR8867631.fastq.gz	Fastqsanger.gz
	SRR8867622.fastq.gz	Fastqsanger.gz
	SRR8867632.fastq.gz	Fastqsanger.gz
	SRR8867623.fastq.gz	Fastqsanger.gz

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Transcriptional responses to interferon require Mediator kinase-dependent pause release and mechanistically distinct functions of CDK8 and CDK19

Project description:Transcriptional responses to interferon require Mediator kinase-dependent pause release and mechanistically distinct functions of CDK8 and CDK19.

2019-07-15 | GSE129501 | GEO

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

Project description: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-? (IFN-?), 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-? responses through its scaffolding function (i.e., it was kinase independent). Accordingly, CDK8, not CDK19, phosphorylates the STAT1 transcription factor (TF) during IFN-? stimulation, and CDK8 kinase inhibition blocked activation of JAK-STAT pathway TFs. Cytokines such as IFN-? rapidly mobilize TFs to "reprogram" cellular transcription; our results implicate CDK8 and CDK19 as essential for this transcriptional reprogramming.

| S-EPMC6842433 | biostudies-literature

Differential Gene Expression in MDA-MB231 from transduction of cells with shRNA targeting CDK19 and CDK8

Project description:When CDK19 was initially discovered, it was assumed that CDK19 played a redundant role to CDK8 because they share 84% amino acid sequence similarity. However, biological clues such as CDK19s different chromosomal location and its more limited tissue distribution suggested a role distinct from CDK8 To investigate whether CDK19 and CDK8 had distinct biological functions in Triple-Negative breast cancer, we knocked down CDK19 and CDK8 in MDA-MB231 and examined differences in the resulting gene expression.

2020-09-13 | GSE103851 | GEO

Knockdown effect of CDK8 and CDK19 in HeLa S3 cell

Project description:Mediator complex has been known as pivotal regulator of RNA polymerase II. Mediator complex has two CDK subunits in vertebrates, named CDK8 and CDK19. To elucidate functional difference between CDK8 and CDK19 in human cell, we employ siRNA mediate knockdown assay using HeLa S3 cell line. According to this assay these CDKs possess highly redundancy in HeLa S3 cell transcription regulation mechanism but in several genes, each CDK shows gene specific regulatory function.

2013-03-16 | GSE45210 | GEO

Knockdown effect of CDK8 or CDK19 in HeLa S3 cell

2011-09-15 | GSE32108 | GEO

Differential Gene Expression in a Patient-Derived Xenograft from transduction of cells with shRNA targeting CDK19 and CDK8

Project description:When CDK19 was initially discovered, it was assumed that CDK19 played a redundant role to CDK8 because they share 84% amino acid sequence similarity. However, biological clues such as CDK19s different chromosomal location and its more limited tissue distribution suggested a role distinct from CDK8 To investigate whether CDK19 and CDK8 had distinct biological functions in Triple-Negative breast cancer, we knocked down CDK19 and CDK8 in a patient-derived xenograft (PDX-C69) and examined differences in the resulting gene expression.

2018-08-01 | GSE85997 | GEO

Transcriptomic analysis of the effects of expression of CDK8/CDK19 and their kinase-inactive mutants in HEK293 cells (WT) and their CDK8/19 double-knockout (dKO) derivatives

Project description:RNA-Seq analysis was carried out to investigate the effects of expression of wild-type CDK8 (CDK8) or CDK19 (CDK19) or their kinase-inactive D173A mutants (CDK8M and CDK19M) in HEK293 cells (WT) and their CDK8/19 double-knockout (dKO) derivatives

2023-06-30 | GSE200753 | GEO

Transcriptomic and Proteomic Effects of CDK8 and CDK19 Mediator Kinases

Project description:Transcriptomic and Proteomic Effects of CDK8 and CDK19 Mediator Kinases

| PRJNA826482 | ENA

Identification of a potent and selective chemical probe for exploring the role of Mediator complex-associated protein kinases CDK8 and CDK19 in human disease [Colo205]

Project description:There is an unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545 a WNT-pathway inhibitor discovered by cell-based screening is a potent and selective chemical probe for the Mediator complex-associated protein kinases CDK8 and CDK19. CCT251545 is an ATP competitive inhibitor with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand binding site. In contrast to Type II inhibitors of CDK8/19 CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogues not only alter WNT-pathway regulated gene expression but also other CDK8/19 targets including STAT1-regulated gene expression. Consistent with this we find that phospho-STAT1SER727 is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally we demonstrate in vivo activity of CCT251545 in WNT-dependent tumours. Colo205 colon cancer cells were treated with 350 nM of Compound 1 or with vehicle (DMSO) for 2 or 6h. Four samples with four biological repeats each. Samples were hybridized against human reference. Compound 1 is a close analogue of a 3,4,5-trisubstituted pyridine series identified from a high-throughput cell-based reporter assay of WNT signalling. It was shown to be potent and selective inhibitor of the Mediator complex-associated protein kinases CDK8 and CDK19. Its is ATP competitive inhibitor with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand-binding site.

2015-10-26 | E-GEOD-67845 | biostudies-arrayexpress

Next Generation Sequencing Quantitative Analysis of Wild Type, CDK8-/-, CDK19-/-, and CDK8-/-CDK19-/- mouse instestinal organoids transcriptomes

Project description:Next Generation Sequencing Quantitative Analysis of Wild Type, CDK8-/-, CDK19-/-, and CDK8-/-CDK19-/- mouse instestinal organoids transcriptomes

| PRJNA773664 | ENA

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