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
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCDK8, K35, cyclin-dependent kinase 8, cyclin dependent kinase 8, IDDHBA
External IDsOMIM: 603184 MGI: 1196224 HomoloGene: 55565 GeneCards: CDK8
Orthologs
SpeciesHumanMouse
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 MbChr 5: 146.17 – 146.24 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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:

References
  1. GRCh38: Ensembl release 89: ENSG00000132964 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000029635 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Tassan JP, Jaquenoud M, Léopold P, Schultz SJ, Nigg EA (Sep 1995). "Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C". Proceedings of the National Academy of Sciences of the United States of America. 92 (19): 8871–5. Bibcode:1995PNAS...92.8871T. doi:10.1073/pnas.92.19.8871. PMC 41069. PMID 7568034.
  6. "Entrez Gene: CDK8 cyclin-dependent kinase 8".
  7. Nemet J, Jelicic B, Rubelj I, Sopta M (Feb 2014). "The two faces of Cdk8, a positive/negative regulator of transcription". Biochimie. 97: 22–7. doi:10.1016/j.biochi.2013.10.004. PMID 24139904.
  8. Poss ZC, Ebmeier CC, Taatjes DJ (2013). "The mediator complex and transcription regulation". Critical Reviews in Biochemistry and Molecular Biology. 48 (6): 575–608. doi:10.3109/10409238.2013.840259. PMC 3852498. PMID 24088064.
  9. Fryer CJ, White JB, Jones KA (Nov 2004). "Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover". Molecular Cell. 16 (4): 509–20. doi:10.1016/j.molcel.2004.10.014. PMID 15546612.
  10. Zhao X, Feng D, Wang Q, Abdulla A, Xie XJ, Zhou J, Sun Y, Yang ES, Liu LP, Vaitheesvaran B, Bridges L, Kurland IJ, Strich R, Ni JQ, Wang C, Ericsson J, Pessin JE, Ji JY, Yang F (Jul 2012). "Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1". The Journal of Clinical Investigation. 122 (7): 2417–27. doi:10.1172/JCI61462. PMC 3386818. PMID 22684109.
  11. Bancerek J, Poss ZC, Steinparzer I, Sedlyarov V, Pfaffenwimmer T, Mikulic I, Dölken L, Strobl B, Müller M, Taatjes DJ, Kovarik P (Feb 2013). "CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response". Immunity. 38 (2): 250–62. doi:10.1016/j.immuni.2012.10.017. PMC 3580287. PMID 23352233.
  12. Gonzalez D, Hamidi N, Del Sol R, Benschop JJ, Nancy T, Li C, Francis L, Tzouros M, Krijgsveld J, Holstege FC, Conlan RS (Feb 2014). "Suppression of Mediator is regulated by Cdk8-dependent Grr1 turnover of the Med3 coactivator". Proceedings of the National Academy of Sciences of the United States of America. 111 (7): 2500–5. Bibcode:2014PNAS..111.2500G. doi:10.1073/pnas.1307525111. PMC 3932902. PMID 24550274.
  13. Grants JM, Ying LT, Yoda A, You CC, Okano H, Sawa H, Taubert S (Feb 2016). "The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans". Genetics. 202 (2): 583–99. doi:10.1534/genetics.115.180265. PMC 4788237. PMID 26715664.
  14. Taatjes DJ, Näär AM, Andel F, Nogales E, Tjian R (Feb 2002). "Structure, function, and activator-induced conformations of the CRSP coactivator". Science. 295 (5557): 1058–62. Bibcode:2002Sci...295.1058T. doi:10.1126/science.1065249. PMID 11834832. S2CID 23446878.
  15. Tsai KL, Sato S, Tomomori-Sato C, Conaway RC, Conaway JW, Asturias FJ (May 2013). "A conserved Mediator-CDK8 kinase module association regulates Mediator-RNA polymerase II interaction". Nature Structural & Molecular Biology. 20 (5): 611–9. doi:10.1038/nsmb.2549. PMC 3648612. PMID 23563140.
  16. Firestein R, Bass AJ, Kim SY, Dunn IF, Silver SJ, Guney I, Freed E, Ligon AH, Vena N, Ogino S, Chheda MG, Tamayo P, Finn S, Shrestha Y, Boehm JS, Jain S, Bojarski E, Mermel C, Barretina J, Chan JA, Baselga J, Tabernero J, Root DE, Fuchs CS, Loda M, Shivdasani RA, Meyerson M, Hahn WC (Sep 2008). "CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity". Nature. 455 (7212): 547–51. Bibcode:2008Natur.455..547F. doi:10.1038/nature07179. PMC 2587138. PMID 18794900.
  17. Donner AJ, Szostek S, Hoover JM, Espinosa JM (Jul 2007). "CDK8 is a stimulus-specific positive coregulator of p53 target genes". Molecular Cell. 27 (1): 121–33. doi:10.1016/j.molcel.2007.05.026. PMC 2936241. PMID 17612495.
  18. Calpena E, Hervieu A, Kaserer T, Swagemakers SMA, Goos JAC, Popoola O, Ortiz-Ruiz MJ, Barbaro-Dieber T, Bownass L, Brilstra EH, Brimble E, Foulds N, Grebe TA, Harder AVE, Lees MM, Monaghan KG, Newbury-Ecob RA, Ong KR, Osio D, Reynoso Santos FJ, Ruzhnikov MRZ, Telegrafi A, van Binsbergen E, van Dooren MF: Deciphering developmental disorders study - van der Spek PJ, Blagg J, Twigg SRF, Mathijssen IM, Clarke PA, Wilkie AOM (2019) De novo missense substitutions in the gene encoding CDK8, a regulator of the mediator complex, cause a syndromic developmental disorder. Am J Hum Genet doi: 10.1016/j.ajhg.2019.02.006
  19. Pelish HE, Liau BB, Nitulescu II, Tangpeerachaikul A, Poss ZC, Da Silva DH, Caruso BT, Arefolov A, Fadeyi O, Christie AL, Du K, Banka D, Schneider EV, Jestel A, Zou G, Si C, Ebmeier CC, Bronson RT, Krivtsov AV, Myers AG, Kohl NE, Kung AL, Armstrong SA, Lemieux ME, Taatjes DJ, Shair MD (Oct 2015). "Mediator kinase inhibition further activates super-enhancer-associated genes in AML". Nature. 526 (7572): 273–6. Bibcode:2015Natur.526..273P. doi:10.1038/nature14904. PMC 4641525. PMID 26416749.
  20. Kang YK, Guermah M, Yuan CX, Roeder RG (Mar 2002). "The TRAP/Mediator coactivator complex interacts directly with estrogen receptors alpha and beta through the TRAP220 subunit and directly enhances estrogen receptor function in vitro". Proceedings of the National Academy of Sciences of the United States of America. 99 (5): 2642–7. Bibcode:2002PNAS...99.2642K. doi:10.1073/pnas.261715899. PMC 122401. PMID 11867769.
  21. Wang G, Cantin GT, Stevens JL, Berk AJ (Jul 2001). "Characterization of mediator complexes from HeLa cell nuclear extract". Molecular and Cellular Biology. 21 (14): 4604–13. doi:10.1128/MCB.21.14.4604-4613.2001. PMC 87123. PMID 11416138.
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Further reading
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