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FLASH GENE
Symbol CDK8 contributors: shn/pgu - updated : 07-05-2019
HGNC name cyclin-dependent kinase 8
HGNC id 1779
EXPRESSION
Type ubiquitous
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestiveesophagus   highly Homo sapiens
 salivary gland   predominantly
Endocrineneuroendocrinepituitary  moderately
Hearing/Equilibriumear   moderately
Urinarybladder   highly Homo sapiens
cell lineage
cell lines
fluid/secretion
at STAGE
physiological period fetal
Text highly in umbilical cord
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a protein kinase domain
  • secondary structure
  • a unique CCNC recognition helix that explains the specificity of the CDK8/CCNC pair
  • mono polymer heteromer , complex
    HOMOLOGY
    interspecies homolog to CDK SRB10, S. cerevisiae
    ortholog to Cdk8, Mus musculus
    intraspecies paralog to CDK19
    Homologene
    FAMILY
  • protein kinase superfamily
  • CMGC Ser/Thr protein kinase family
  • CDC2/CDKX subfamily
  • transcription-regulating CDK family
  • CATEGORY enzyme , regulatory , transcription factor , protooncogene
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome,nucleosome
    intracellular,nucleus,nucleolus
    basic FUNCTION
  • acting as a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes
  • functioning as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery
  • recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors
  • phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex
  • phosphorylating CCNH leading to down-regulation of the TFIIH complex and transcriptional repression
  • recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation
  • CDK8/cyclin C can regulate transcription by targeting the CDK7/cyclin H subunits of the general transcription initiation factor IIH
  • CDK8 functions as a positive regulator of p21 and HDM2 transcription
  • CDK8 kinase activity is necessary for beta-catenin-driven transformation and for expression of several beta-catenin transcriptional targets
  • CDK8 is a histone H3 kinase, when associated with Mediator
  • CDK8 plays important roles in gene regulation and is a colorectal cancer oncogene that regulates b-catenin activity
  • functioning as a coactivator within the TP53 transcriptional program
  • with CDK11B possess opposing functions in viral activator VP16-dependent transcriptional regulation
  • stimulus-specific positive coregulator of TP53 target genes
  • role for CDK8 in transcriptional regulation that may contribute to its oncogenic effects
  • involved in the regulation of mRNA transcription and was identified as a potent oncogene in colon cancerogenesis
  • CDK8 inhibits Notch acetylation and Notch transcription enhanced by EP300
  • CDK8 supported transcriptional activation, whereas CDK19, however, counteracted it
  • cyclin-dependent kinase that mediates transcriptional control of pathways linked to both cancer and stem cells
  • enzymatically active CDK8 is responsible for suppression of GLI3 transactivation activity, and further, MED12 most likely contributes to this suppression through its role as an anchor for CDK8 in Mediator
  • functions as an oncoprotein in melanoma and colorectal cancers, but plays a tumor-suppressive role in endometrial cancers
  • implicated as a regulator of multiple steps in cell cycle progression
  • mediator-associated kinase required for induction of many HIF1A target genes
  • CDK8 module could positively regulate transcription by modulating Mediator conformation
  • has emerged as a key regulator of multiple transcriptional programs linked to nutrient/growth factor sensing and differentiation control
  • CDK8 functions to suppress de novo lipogenesis, that is often elevated in non-alcoholic fatty liver disease (NAFLD) and insulin resistance
  • CDK8 and its paralog CDK19, in complex with CCNC, MED12 and MED13, are transcriptional regulators that mediate several carcinogenic pathways and the chemotherapy-induced tumor-supporting paracrine network
  • function for CDK8 and CDK19 in regulating innate immune activation,suggesting that these kinases may warrant consideration as therapeutic targets for inflammatory disorders
  • CDK8 and its paralog CDK19, associated with the transcriptional Mediator complex, act as coregulators of several transcription factors implicated in cancer
  • 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
  • CDK8 activates or represses transcription by associating with the mediator complex or by regulating transcription factors
  • suppressive effect of CDK8 on NK-cell activity
  • regulates transcriptional process via associating with the mediator complex or phosphorylating transcription factors (TF)
  • CDK8 and CDK19, collectively termed 'Mediator Kinase,' are cyclin-dependent kinases that have been implicated as key rheostats in cellular homeostasis and developmental programming
  • CELLULAR PROCESS cell cycle, progression
    nucleotide, replication
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    text control of cell cycle progression
    PATHWAY
    metabolism
    signaling
    a component
  • mediator complex including CDK8, CCNC, RNA polymerase II
  • CDK8 subcomplex” (containing CDK8, cyclin C, MED12, and MED13), functioning as a simple switch that controls the Mediator–pol II interaction to help regulate transcription initiation and reinitiation events
  • INTERACTION
    DNA
    RNA
    small molecule metal binding, cofactor, nucleotide,
  • Mg2+
  • ATP
  • protein
  • phosphorylating cyclin H, repressing the ability of GTF2H to activate transcription and its C-terminal kinase activity
  • interacting with CTNNB1, GLI3 and MAML1
  • cyclin C
  • CDK8, cyclin C, MED12, and MED13 can associate with Mediator and are presumed to form a stable "CDK8 subcomplex"
  • is a regulatory partner of CCNC
  • MAML1 plays a key role in recruiting CDK8 to phosphorylate Notch1 ICD (intracellular domain) and subsequent degradation via the FBXW7 ubiquitin ligase
  • acts, at least in part, through MYC to maintain both tumors and embryonic stem cells in an undifferentiated state
  • role for enzymatically active CDK8 in suppression of GLI3 transactivation activity
  • MED13/MED13L physically link the CDK8 module to Mediator, and FBXW7 loss increases CDK8 module-Mediator association
  • mechanistic link between HIF1A and CDK8, two potent oncogenes, in the cellular response to hypoxia
  • CDK8 and CDK19, individually interact with PRMT5 and WDR77, and their interactions with PRMT5 cause transcriptional repression of CEBPB target genes by regulating symmetric dimethylation of histone H4 arginine 3 (H4R3me2s) in the promoter regions of those genes
  • MTOR is a critical regulator of CDK8 and its activating partner CCNC
  • ZYX promotes colon cancer tumorigenesis in a mitotic-phosphorylation-dependent manner and through CDK8-mediated YAP1 activation
  • cell & other
    REGULATION
    activated by cyclin C (CCNC)
    ASSOCIATED DISORDERS
    corresponding disease(s) MRSCF
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   amplification --over  
    colon cancers
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
  • CDK8 may identify a subset of colon cancer patients with a poor prognosis
  • Therapy target
    SystemTypeDisorderPubmed
    cancer  
    targeting CDK8 therapeutically may specifically inhibit the stem-like properties of cancer cells
    cancer  
    potential target for developing novel CDK8 inhibitors in cancer therapeutics
    cancermetastases 
    blocking CDK8/19 specifically abrogates tumor cell invasion, changes in EMT-associated transcription factors
    ANIMAL & CELL MODELS
    ablation of the CDK8 kinase in mice results in lethality at the preimplantation stage