Cyclin-dependent kinase 8

Cell division protein kinase 8 is an enzyme that in humans is encoded by the CDK8 gene.^[5][6]

CDK8
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3RGF, 4F6S, 4F6U, 4F6W, 4F70, 4F7J, 4F7L, 4F7N, 4F7S, 4G6L, 4CRL, 5HBH, 5CEI, 5FGK, 5HBE, 5BNJ, 5HBJ, 5HVY, 5HNB, 5I5Z
Identifiers
Aliases	CDK8, K35, cyclin-dependent kinase 8, cyclin dependent kinase 8, IDDHBA
External IDs	OMIM: 603184; MGI: 1196224; HomoloGene: 55565; GeneCards: CDK8; OMA:CDK8 - orthologs
Gene location (Human) Chr. Chromosome 13 (human)[1] Band 13q12.13 Start 26,254,104 bp[1] End 26,405,238 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5|5 G3 Start 146,168,040 bp[2] End 146,239,684 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in buccal mucosa cell secondary oocyte sperm parietal pleura endothelial cell muscle layer of sigmoid colon visceral pleura amniotic fluid jejunal mucosa ganglionic eminence Top expressed in ureter secondary oocyte primitive streak zygote medullary collecting duct mandibular prominence Paneth cell somite vestibular sensory epithelium maxillary prominence More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity protein kinase activity nucleotide binding kinase activity protein binding RNA polymerase II CTD heptapeptide repeat kinase activity ATP binding protein serine/threonine kinase activity cyclin-dependent protein serine/threonine kinase activity Cellular component mediator complex nucleoplasm nucleus nucleolus protein-containing complex Biological process regulation of transcription, DNA-templated phosphorylation protein phosphorylation transcription initiation from RNA polymerase II promoter positive regulation of transcription by RNA polymerase II transcription, DNA-templated regulation of mitotic cell cycle regulation of cell cycle Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1024 264064 Ensembl ENSG00000132964 ENSMUSG00000029635 UniProt P49336 Q8R3L8 RefSeq (mRNA) NM_001260 NM_001318368 NM_001346501 NM_153599 NM_181570 NM_001359990 NM_001359991 RefSeq (protein) NP_001251 NP_001305297 NP_001333430 NP_705827 NP_001346919 NP_001346920 Location (UCSC) Chr 13: 26.25 – 26.41 Mb Chr 5: 146.17 – 146.24 Mb PubMed search [3] [4]
Wikidata
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Function

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 several mechanisms. CDK8 binds to and/or phosphorylates several transcription factors, which can have an activating or inhibitory effect on transcription factor function.^[7][8] CDK8 phosphorylates the Notch intracellular domain,^[9] SREBP,^[10] and STAT1 S727.^[11] CDK8 also inhibits transcriptional activation by influencing turnover of subunits in the mediator complex tail module.^[12][13] In addition, CDK8 influences binding of RNA polymerase II to the mediator complex.^[14][15]

Clinical significance

CDK8 is a colorectal cancer oncogene: the CDK8 gene is amplified in human colorectal tumors, activating β-catenin-mediated transcription that drives colon tumorigenesis.^[16] However, CDK8 may not be oncogenic in all cell types, and indeed may act as a tumor suppressor in the notch and EGFR signaling pathways. Specifically, CDK8 promotes turnover of the notch intracellular domain,^[9] and inhibits EGFR signaling-driven cell fates in C. elegans.^[13] Thus, CDK8 may be an oncogene in cancers driven by Wnt/β-catenin signaling, but could instead be a tumor suppressor gene in cancers driven by notch or EGFR signaling. In addition, CDK8 promotes transcriptional activation mediated by the tumor suppressor protein p53, indicating that it may have an important role in tumor suppression ^[17] Further research is needed to delineate the effects of CDK8 inhibition in different tissues, so for the time being, drugs targeting CDK8 for cancer treatment remain untested in humans.

An autosomal dominant syndrome has been described that is associated with mutations in the ATP binding pocket of the kinase domain.^[18] The clinical features include agenesis of the corpus callosum, mild to moderate intellectual disability, hypotonia, seizures, hearing or visual impairments, behavioral disorders, variable facial dysmorphism, congenital heart disease and ano-rectal malformations.

As a potential drug target

The natural product cortistatin A is a potent and selective inhibitor of CDK8 and CDK19.^[19] Inhibition of CDK8 and CDK19 with cortistatin A suppresses AML cell growth and has anticancer activity in animal models of AML by causing selective and disproportionate up regulation of super-enhancer-associated genes including the cell identity genes CEBPA and IRF8.

Interactions

Cyclin-dependent kinase 8 has been shown to interact with:

• CCNC^{[5][20][21][22][23]}
• CREB binding protein^[22]
• CRSP3^[20][21]
• MED1^[20][24]
• MED12^[20][24]
• MED14^[21][24]
• MED16^[20][24]
• MED17^[20][24]
• MED21^{[20][22][24][25]}
• MED24^[20][24]
• MED26^[26]
• MED6^{[20][21][24][27]}
• Notch proteins^[9]
• POLR2A^[22]
• SMARCB1^[22]
• STAT1^[11]
• SREBP^[10]