CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

The nuclear factor-kappa B (NF kappa B) family of transcription factors has been implicated in inflammatory disorders, viral infections, and cancer. Most of the drugs that inhibit NF kappa B show significant side effects, possibly due to sustained NF kappa B suppression. Drugs affecting induced, but not basal, NF kappa B activity may have the potential to provide therapeutic benefit without associated toxicity. NF kappa 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 kappa B-induced transcription when such transcription is activated by p21-independent canonical inducers, such as TNF alpha. On NF kappa B activation, CDK8/19 are corecruited with NF kappa 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 kappa B include IL8, CXCL1, and CXCL2, which encode tumor-promoting proinflammatory cytokines. Although it suppressed newly induced NF kappa B-driven transcription, CDK8/19 inhibition in most cases had no effect on the basal expression of NF kappa 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.