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Cyclin-dependent kinase 8 positively cooperates with Mediator to promote thyroid hormone receptor-dependent transcriptional activation.
Mol Cell Biol. 2010 May; 30(10):2437-48.MC

Abstract

Mediator is a multisubunit assemblage of proteins originally identified in humans as a coactivator bound to thyroid hormone receptors (TRs) and essential for thyroid hormone (T3)-dependent transcription. Cyclin-dependent kinase 8 (CDK8), cyclin C, MED12, and MED13 form a variably associated Mediator subcomplex (termed the CDK8 module) whose functional role in TR-dependent transcription remains unclear. Using in vitro and cellular approaches, we show here that Mediator complexes containing the CDK8 module are specifically recruited into preinitiation complexes at the TR target gene type I deiodinase (DioI) together with RNA polymerase II (Pol II) in a TR- and T3-dependent manner. We found that CDK8 is essential for robust T3-dependent Dio1 transcription and that CDK8 knockdown via RNA interference decreased Pol II occupancy, and also the recruitment of the Pol II kinase CDK9, at the DioI promoter. Chromatin immunoprecipitation revealed CDK8 occupancy at the DioI promoter concurrent with active transcription, thus suggesting CDK8 involvement in transcriptional reinitiation. Mutagenesis assays showed that CDK8 kinase activity is necessary for full T3-dependent DioI activation, whereas in vitro kinase studies indicated that CDK8 may contribute to Pol II phosphorylation. Collectively, our data suggest CDK8 plays an important coactivator role in TR-dependent transcription by promoting Pol II recruitment and activation at TR target gene promoters.

Authors+Show Affiliations

Department of Physiology and Biophysics, Robert Wood Johnson Medical School, UMDNJ, Piscataway, New Jersey 08854, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

20231357

Citation

Belakavadi, Madesh, and Joseph D. Fondell. "Cyclin-dependent Kinase 8 Positively Cooperates With Mediator to Promote Thyroid Hormone Receptor-dependent Transcriptional Activation." Molecular and Cellular Biology, vol. 30, no. 10, 2010, pp. 2437-48.
Belakavadi M, Fondell JD. Cyclin-dependent kinase 8 positively cooperates with Mediator to promote thyroid hormone receptor-dependent transcriptional activation. Mol Cell Biol. 2010;30(10):2437-48.
Belakavadi, M., & Fondell, J. D. (2010). Cyclin-dependent kinase 8 positively cooperates with Mediator to promote thyroid hormone receptor-dependent transcriptional activation. Molecular and Cellular Biology, 30(10), 2437-48. https://doi.org/10.1128/MCB.01541-09
Belakavadi M, Fondell JD. Cyclin-dependent Kinase 8 Positively Cooperates With Mediator to Promote Thyroid Hormone Receptor-dependent Transcriptional Activation. Mol Cell Biol. 2010;30(10):2437-48. PubMed PMID: 20231357.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cyclin-dependent kinase 8 positively cooperates with Mediator to promote thyroid hormone receptor-dependent transcriptional activation. AU - Belakavadi,Madesh, AU - Fondell,Joseph D, Y1 - 2010/03/15/ PY - 2010/3/17/entrez PY - 2010/3/17/pubmed PY - 2010/6/3/medline SP - 2437 EP - 48 JF - Molecular and cellular biology JO - Mol Cell Biol VL - 30 IS - 10 N2 - Mediator is a multisubunit assemblage of proteins originally identified in humans as a coactivator bound to thyroid hormone receptors (TRs) and essential for thyroid hormone (T3)-dependent transcription. Cyclin-dependent kinase 8 (CDK8), cyclin C, MED12, and MED13 form a variably associated Mediator subcomplex (termed the CDK8 module) whose functional role in TR-dependent transcription remains unclear. Using in vitro and cellular approaches, we show here that Mediator complexes containing the CDK8 module are specifically recruited into preinitiation complexes at the TR target gene type I deiodinase (DioI) together with RNA polymerase II (Pol II) in a TR- and T3-dependent manner. We found that CDK8 is essential for robust T3-dependent Dio1 transcription and that CDK8 knockdown via RNA interference decreased Pol II occupancy, and also the recruitment of the Pol II kinase CDK9, at the DioI promoter. Chromatin immunoprecipitation revealed CDK8 occupancy at the DioI promoter concurrent with active transcription, thus suggesting CDK8 involvement in transcriptional reinitiation. Mutagenesis assays showed that CDK8 kinase activity is necessary for full T3-dependent DioI activation, whereas in vitro kinase studies indicated that CDK8 may contribute to Pol II phosphorylation. Collectively, our data suggest CDK8 plays an important coactivator role in TR-dependent transcription by promoting Pol II recruitment and activation at TR target gene promoters. SN - 1098-5549 UR - https://www.unboundmedicine.com/medline/citation/20231357/Cyclin_dependent_kinase_8_positively_cooperates_with_Mediator_to_promote_thyroid_hormone_receptor_dependent_transcriptional_activation_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=20231357 DB - PRIME DP - Unbound Medicine ER -