The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK8 and cyclin C associate with the Mediator complex and regulate transcription by currently not well-understood mechanisms. Only a few direct substrates of CDK8 have been identified and validated by independent studies. One such CDK8 substrate is STAT1 S727.
The natural product cortistatin A is a highly potent and selective inhibitor of CDK8 and its highly similar homolog CDK19. Inhibition of CDK8 and CDK19 with cortistatin A potently suppresses growth AML cells and has significant anti-leukemic activity in vivo. Inhibition of CDK8 and CDK19 is a new therapeutic approach to AML. Inhibition of CDK8/CDK19 in AML causes selective and disproportionate up regulation of super-enhancer-associated genes including the cell identity genes CEBPA and IRF8. These effects contribute to the anti-leukemic activity of cortistatin A and reveal that CDK8/19 restrain heightened activation of specific super-enhancer-associated genes in AML.
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