CDK8
Description
The CDK8 (cyclin dependent kinase 8) is a protein-coding gene located on chromosome 13.
Cell division protein kinase 8 (CDK8) is an enzyme encoded by the CDK8 gene in humans. It belongs to the cyclin-dependent protein kinase (CDK) family. CDK8 forms a complex with cyclin C and interacts with the Mediator complex, a crucial component of transcription regulation. This complex influences transcription by various mechanisms. CDK8 binds to and/or phosphorylates several transcription factors, leading to either activation or inhibition of their function. For instance, CDK8 phosphorylates the Notch intracellular domain, SREBP, and STAT1 S727. CDK8 also inhibits transcriptional activation by altering the turnover of subunits within the mediator complex tail module. Additionally, it influences the binding of RNA polymerase II to the Mediator complex. CDK8 has been implicated in colorectal cancer as an oncogene, with its gene amplified in human colorectal tumors. This amplification activates β-catenin-mediated transcription, driving colon tumorigenesis. However, CDK8 may not be oncogenic in all cell types and may even function as a tumor suppressor in the notch and EGFR signaling pathways. Specifically, CDK8 promotes the turnover of the notch intracellular domain and inhibits EGFR signaling-driven cell fates in C. elegans.
CDK8 is a component of the Mediator complex, a vital coactivator that regulates gene transcription for most RNA polymerase II-dependent genes. Mediator acts as a bridge, transmitting information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interaction with regulatory proteins, forming a scaffold for assembling a functional pre-initiation complex involving RNA polymerase II and general transcription factors. CDK8 phosphorylates the CTD (C-terminal domain) of the RNA polymerase II large subunit, which can potentially inhibit the formation of a transcription initiation complex. CDK8 also phosphorylates CCNH, leading to down-regulation of the TFIIH complex and subsequent transcriptional repression. CDK8 is recruited via interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, triggering its degradation.
CDK8 is also known as IDDHBA, K35.
