CDK8/19 Mediator kinases potentiate induction of transcription by NF?B.

ABSTRACT: The nuclear factor-?B (NF?B) family of transcription factors has been implicated in inflammatory disorders, viral infections, and cancer. Most of the drugs that inhibit NF?B show significant side effects, possibly due to sustained NF?B suppression. Drugs affecting induced, but not basal, NF?B activity may have the potential to provide therapeutic benefit without associated toxicity. NF?B activation by stress-inducible cell cycle inhibitor p21 was shown to be mediated by a p21-stimulated transcription-regulating kinase CDK8. CDK8 and its paralog CDK19, associated with the transcriptional Mediator complex, act as coregulators of several transcription factors implicated in cancer; CDK8/19 inhibitors are entering clinical development. Here we show that CDK8/19 inhibition by different small-molecule kinase inhibitors or shRNAs suppresses the elongation of NF?B-induced transcription when such transcription is activated by p21-independent canonical inducers, such as TNF?. On NF?B activation, CDK8/19 are corecruited with NF?B to the promoters of the responsive genes. Inhibition of CDK8/19 kinase activity suppresses the RNA polymerase II C-terminal domain phosphorylation required for transcriptional elongation, in a gene-specific manner. Genes coregulated by CDK8/19 and NF?B include IL8, CXCL1, and CXCL2, which encode tumor-promoting proinflammatory cytokines. Although it suppressed newly induced NF?B-driven transcription, CDK8/19 inhibition in most cases had no effect on the basal expression of NF?B-regulated genes or promoters; the same selective regulation of newly induced transcription was observed with other transcription signals potentiated by CDK8/19. This selective role of CDK8/19 identifies these kinases as mediators of transcriptional reprogramming, a key aspect of development and differentiation as well as pathological processes.

SUBMITTER: Chen M 

PROVIDER: S-EPMC5617299 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature