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
View/Edit Human View/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:

• 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]

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.
22. 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. doi:10.1128/MCB.18.9.5355. PMC 109120. PMID 9710619.
23. 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.
24. 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.
25. 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. doi:10.1128/MCB.17.10.6029. PMC 232452. PMID 9315662.
26. 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.
27. 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. Bibcode:2004PNAS..101.2339Y. doi:10.1073/pnas.0308676100. PMC 356952. PMID 14983011.

Further reading

• Schultz SJ, Nigg EA (Oct 1993). "Identification of 21 novel human protein kinases, including 3 members of a family related to the cell cycle regulator nimA of Aspergillus nidulans". Cell Growth & Differentiation. 4 (10): 821–30. PMID 8274451.
• Rickert P, Seghezzi W, Shanahan F, Cho H, Lees E (Jun 1996). "Cyclin C/CDK8 is a novel CTD kinase associated with RNA polymerase II". Oncogene. 12 (12): 2631–40. PMID 8700522.
• Cujec TP, Cho H, Maldonado E, Meyer J, Reinberg D, Peterlin BM (Apr 1997). "The human immunodeficiency virus transactivator Tat interacts with the RNA polymerase II holoenzyme". Molecular and Cellular Biology. 17 (4): 1817–23. doi:10.1128/MCB.17.4.1817. PMC 232028. PMID 9121429.
• Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, Livingston DM, Parvin JD (May 1997). "BRCA1 is a component of the RNA polymerase II holoenzyme". Proceedings of the National Academy of Sciences of the United States of America. 94 (11): 5605–10. Bibcode:1997PNAS...94.5605S. doi:10.1073/pnas.94.11.5605. PMC 20825. PMID 9159119.
• Neish AS, Anderson SF, Schlegel BP, Wei W, Parvin JD (Feb 1998). "Factors associated with the mammalian RNA polymerase II holoenzyme". Nucleic Acids Research. 26 (3): 847–53. doi:10.1093/nar/26.3.847. PMC 147327. PMID 9443979.
• 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. doi:10.1128/MCB.18.9.5355. PMC 109120. PMID 9710619.
• Sun X, Zhang Y, Cho H, Rickert P, Lees E, Lane W, Reinberg D (Aug 1998). "NAT, a human complex containing Srb polypeptides that functions as a negative regulator of activated transcription". Molecular Cell. 2 (2): 213–22. doi:10.1016/S1097-2765(00)80131-8. PMID 9734358.
• Rickert P, Corden JL, Lees E (Jan 1999). "Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases". Oncogene. 18 (4): 1093–102. doi:10.1038/sj.onc.1202399. PMID 10023686.
• Gu W, Malik S, Ito M, Yuan CX, Fondell JD, Zhang X, Martinez E, Qin J, Roeder RG (Jan 1999). "A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation". Molecular Cell. 3 (1): 97–108. doi:10.1016/S1097-2765(00)80178-1. PMID 10024883.
• 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.
• Rachez C, Lemon BD, Suldan Z, Bromleigh V, Gamble M, Näär AM, Erdjument-Bromage H, Tempst P, Freedman LP (Apr 1999). "Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex". Nature. 398 (6730): 824–8. Bibcode:1999Natur.398..824R. doi:10.1038/19783. PMID 10235266. S2CID 204992765.
• Akoulitchev S, Chuikov S, Reinberg D (Sep 2000). "TFIIH is negatively regulated by cdk8-containing mediator complexes". Nature. 407 (6800): 102–6. Bibcode:2000Natur.407..102A. doi:10.1038/35024111. PMID 10993082. S2CID 4430185.
• Ramanathan Y, Rajpara SM, Reza SM, Lees E, Shuman S, Mathews MB, Pe'ery T (Apr 2001). "Three RNA polymerase II carboxyl-terminal domain kinases display distinct substrate preferences". The Journal of Biological Chemistry. 276 (14): 10913–20. doi:10.1074/jbc.M010975200. PMID 11278802.
• 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.
• Di Pietro C, Rapisarda A, Bonaiuto C, Lizzio MN, Engel H, Amico V, Scalia M, Amato A, Grzeschik KH, Sichel G, Purrello M (May 1999). "Genomics of the human genes encoding four TAFII subunits of TFIID, the three subunits of TFIIA, as well as CDK8 and SURB7". Somatic Cell and Molecular Genetics. 25 (3): 185–9. doi:10.1023/A:1018897624615. PMID 11441538. S2CID 42316067.
• Vogel L, Baratte B, Détivaud L, Azzi L, Leopold P, Meijer L (Apr 2002). "Molecular cloning and characterisation of p15(CDK-BP), a novel CDK-binding protein". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1589 (2): 219–31. doi:10.1016/S0167-4889(02)00175-1. PMID 12007796.
• Crowley TE, Kaine EM, Yoshida M, Nandi A, Wolgemuth DJ (Aug 2002). "Reproductive cycle regulation of nuclear import, euchromatic localization, and association with components of Pol II mediator of a mammalian double-bromodomain protein". Molecular Endocrinology. 16 (8): 1727–37. doi:10.1210/me.2001-0353. PMID 12145330.
• Sato S, Tomomori-Sato C, Banks CA, Sorokina I, Parmely TJ, Kong SE, Jin J, Cai Y, Lane WS, Brower CS, Conaway RC, Conaway JW (Apr 2003). "Identification of mammalian Mediator subunits with similarities to yeast Mediator subunits Srb5, Srb6, Med11, and Rox3" (PDF). The Journal of Biological Chemistry. 278 (17): 15123–7. doi:10.1074/jbc.C300054200. PMID 12584197. S2CID 41400940.

External links

• CDK8+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• CDK8 human gene location in the UCSC Genome Browser.
• CDK8 human gene details in the UCSC Genome Browser.