Cyclin-dependent kinase 8

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CDK8
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CDK8, K35, cyclin-dependent kinase 8
External IDs MGI: 1196224 HomoloGene: 55565 GeneCards: 1024
RNA expression pattern
PBB GE CDK8 204831 at tn.png

PBB GE PNPLA6 203718 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001260
NM_001318368

NM_153599
NM_181570

RefSeq (protein)

NP_001251.1
NP_001305297.1

NP_705827.2

Location (UCSC) Chr 13: 26.25 – 26.41 Mb Chr 5: 146.23 – 146.3 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Cell division protein kinase 8 is an enzyme that in humans is encoded by the CDK8 gene.[1][2]

Function[edit]

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.[3][4] CDK8 phosphorylates the Notch intracellular domain,[5] SREBP,[6] and STAT1 S727.[7] CDK8 also inhibits transcriptional activation by influencing turnover of subunits in the mediator complex tail module.[8][9] In addition, CDK8 influences binding of RNA polymerase II to the mediator complex.[10][11]

Clinical significance[edit]

CDK8 is a colorectal cancer oncogene: the CDK8 gene is amplified in human colorectal tumors, activating β-catenin-mediated transcription that drives colon tumorigenesis.[12] 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,[5] and inhibits EGFR signaling-driven cell fates in C. elegans.[9] 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 [13] 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.

As a potential drug target[edit]

The natural product cortistatin A is a potent and selective inhibitor of CDK8 and CDK19.[14] 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[edit]

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

References[edit]

  1. ^ a b 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. doi:10.1073/pnas.92.19.8871. PMC 41069. PMID 7568034. 
  2. ^ "Entrez Gene: CDK8 cyclin-dependent kinase 8". 
  3. ^ 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. 
  4. ^ Poss ZC, Ebmeier CC, Taatjes DJ. "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. 
  5. ^ a b c 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. 
  6. ^ a b 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. 
  7. ^ a b 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. 
  8. ^ 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. doi:10.1073/pnas.1307525111. PMC 3932902. PMID 24550274. 
  9. ^ a b 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. PMID 26715664. 
  10. ^ 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. doi:10.1126/science.1065249. PMID 11834832. 
  11. ^ 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. 
  12. ^ 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. doi:10.1038/nature07179. PMC 2587138. PMID 18794900. 
  13. ^ 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. 
  14. ^ 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. doi:10.1038/nature14904. PMID 26416749. 
  15. ^ a b c d e f g h i 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. doi:10.1073/pnas.261715899. PMC 122401. PMID 11867769. 
  16. ^ a b c d 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. 
  17. ^ a b c d e Cho H, Orphanides G, Sun X, Yang XJ, Ogryzko V, Lees E, Nakatani Y, Reinberg D (Sep 1998). "A human RNA polymerase II complex containing factors that modify chromatin structure". Molecular and Cellular Biology 18 (9): 5355–63. PMC 109120. PMID 9710619. 
  18. ^ Zhang Y, Iratni R, Erdjument-Bromage H, Tempst P, Reinberg D (May 1997). "Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex". Cell 89 (3): 357–64. doi:10.1016/s0092-8674(00)80216-0. PMID 9150135. 
  19. ^ a b c d e f g h Ito M, Yuan CX, Malik S, Gu W, Fondell JD, Yamamura S, Fu ZY, Zhang X, Qin J, Roeder RG (Mar 1999). "Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators". Molecular Cell 3 (3): 361–70. doi:10.1016/s1097-2765(00)80463-3. PMID 10198638. 
  20. ^ Suñé C, Hayashi T, Liu Y, Lane WS, Young RA, Garcia-Blanco MA (Oct 1997). "CA150, a nuclear protein associated with the RNA polymerase II holoenzyme, is involved in Tat-activated human immunodeficiency virus type 1 transcription". Molecular and Cellular Biology 17 (10): 6029–39. PMC 232452. PMID 9315662. 
  21. ^ Sato S, Tomomori-Sato C, Parmely TJ, Florens L, Zybailov B, Swanson SK, Banks CA, Jin J, Cai Y, Washburn MP, Conaway JW, Conaway RC (Jun 2004). "A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology". Molecular Cell 14 (5): 685–91. doi:10.1016/j.molcel.2004.05.006. PMID 15175163. 
  22. ^ Yang F, DeBeaumont R, Zhou S, Näär AM (Feb 2004). "The activator-recruited cofactor/Mediator coactivator subunit ARC92 is a functionally important target of the VP16 transcriptional activator". Proceedings of the National Academy of Sciences of the United States of America 101 (8): 2339–44. doi:10.1073/pnas.0308676100. PMC 356952. PMID 14983011. 

Further reading[edit]

External links[edit]