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FLASH GENE
Symbol CDK8 contributors: shn/pgu - updated : 07-05-2019
HGNC name cyclin-dependent kinase 8
HGNC id 1779
Corresponding disease
MRSCF mental retardation syndromic with cerebral malformation and facial dysmorphism
Location 13q12.13      Physical location : 26.828.755 - 26.978.569
Synonym name
  • mediator complex subunit CDK8
  • protein kinase K35
  • cell division protein kinase 8
  • mediator of RNA polymerase II transcription subunit CDK8
  • Synonym symbol(s) K35, MGC126074, MGC126075
    EC.number 2.7.11.23, 2.7.11.22
    DNA
    TYPE functioning gene
    STRUCTURE 151.13 kb     13 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence cytosine-phosphate-guanine/HTF
    MAPPING cloned Y linked N status confirmed
    Map By screening a human testis cDNA library with K35 , CDK8 was mapped to chromosome 13q12. cen - D13S1294 - D13S221 - CDK8 - D13S1304 - D13S1254 - qter
    Authors PMID: 7568034
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    13 - 3101 53.2 464 - 2007 17612495
    13 - 3098 - 463 - 2007 17612495
    12 - 3043 - 291 - 2007 17612495
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivesalivary gland   predominantly
    Endocrineneuroendocrinepituitary  moderately
    Hearing/Equilibriumear   moderately
    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