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PMID: 20098423 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

CDK8 is a positive regulator of transcriptional elongation within the serum response network.

Nature structural & molecular biology ·Vol. 17 ·No. 2 ·2010-02-00 ·Pages 194-201

Donner AJ, Ebmeier CC, Taatjes DJ, Espinosa JM

Abstract

The Mediator complex allows communication between transcription factors and RNA polymerase II (RNAPII). Cyclin-dependent kinase 8 (CDK8), the kinase found in some variants of Mediator, has been characterized mostly as a transcriptional repressor. Recently, CDK8 was demonstrated to be a potent oncoprotein. Here we show, using a human tumor cell line, that CDK8 is a positive regulator of genes within the serum response network, including several members of the activator protein 1 and early growth response family of oncogenic transcription factors. Mechanistic studies show that CDK8 is not required for RNAPII recruitment or promoter escape. Instead, CDK8 depletion leads to the appearance of slower elongation complexes carrying hypophosphorylated RNAPII. CDK8-Mediator regulates precise steps in the assembly of the RNAPII elongation complex, including the recruitment of positive transcription elongation factor b and BRD4. Furthermore, CDK8-Mediator specifically interacts with positive transcription elongation factor b. Thus, we have uncovered a role for CDK8 in transcriptional regulation that may contribute to its oncogenic effects.

MeSH Terms
Cell Cycle Proteins Cell Line, Tumor Cyclin-Dependent Kinase 8/genetics,physiology Gene Knockdown Techniques Humans Nuclear Proteins/metabolism Positive Transcriptional Elongation Factor B/metabolism Protein Binding Protein Interaction Mapping RNA Polymerase II/metabolism Serum Response Element Serum Response Factor/metabolism Trans-Activators/physiology Transcription Factor AP-1/metabolism Transcription Factors/metabolism Transcription, Genetic
Chemicals
BRD4 protein, human Cell Cycle Proteins Nuclear Proteins Serum Response Factor Trans-Activators Transcription Factor AP-1 Transcription Factors Positive Transcriptional Elongation Factor B CDK8 protein, human Cyclin-Dependent Kinase 8 RNA Polymerase II
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Donner Aaron J
Howard Hughes Medical Institute, The University of Colorado at Boulder, Boulder, Colorado, USA.
Ebmeier Christopher C
Taatjes Dylan J
Espinosa Joaquín M
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Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb.1752
Published
2010-02-00
Epub
2010-00-24
Pages
194-201
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC2920286
Subset
IM
Grants
NCI NIH HHS · R01 CA117907-04 · United States
NCI NIH HHS · P01 CA112131 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · CA117907 · United States
NIGMS NIH HHS · T32GM07135 · United States
NIGMS NIH HHS · T32 GM007135 · United States
NCI NIH HHS · P01 CA112181 · United States
NCI NIH HHS · R01 CA117907 · United States
Databases
GEO
GSE19199
External Links
PubMed source DOI: 10.1038/nsmb.1752 PMC Full Text View journal details
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