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

Nature Structural & Molecular Biology volume 17, pages 194201 (2010) | Download Citation

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.

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Acknowledgements

This work was supported initially by a grant from the US National Institutes of Health (NIH; CA117907) and later by a grant from the US National Science Foundation (MCB-0842974) to the Espinosa laboratory. J.M.E. is a Howard Hughes Medical Institute Early Career Scientist. Work in the Taatjes laboratory is supported by grants from the NIH (PO1 CA112131) and the Ellison Medical Foundation. A.J.D. and C.C.E. were supported in part by NIH training grant T32GM07135. We are thankful to members of the Espinosa laboratory for contributing ideas and support, especially M. Sechler and C. Potts for technical assistance and N. Gomes for discussion.

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Affiliations

  1. Howard Hughes Medical Institute, The University of Colorado at Boulder, Boulder, Colorado, USA.

    • Aaron J Donner
    •  & Joaquín M Espinosa
  2. Department of Molecular, Cellular and Developmental Biology, The University of Colorado at Boulder, Boulder, Colorado, USA.

    • Aaron J Donner
    •  & Joaquín M Espinosa
  3. Department of Chemistry and Biochemistry, The University of Colorado at Boulder, Boulder, Colorado, USA.

    • Christopher C Ebmeier
    •  & Dylan J Taatjes

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Contributions

A.J.D. performed most ChIP, Q-RT-PCR and western blot experiments, performed all nuclear run-ons, carried out microarray data analysis and wrote the manuscript. C.C.E. and D.T. generated all data regarding the CDK8-Mediator–P-TEFb interaction. J.M.E. performed ChIP, Q-RT-PCR and western blot experiments and carried out the microarray experiment.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Joaquín M Espinosa.

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https://doi.org/10.1038/nsmb.1752

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