Cyclin-dependent kinase 8

Cyclin-dependent kinase 8
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3RGF​, 4F6S​, 4F6U​, 4F6W​, 4F70​, 4F7J​, 4F7L​, 4F7N​, 4F7S​, 4G6L​
Identifiers
Symbols	CDK8 ; K35
External IDs	OMIM: 603184 MGI: 1196224 HomoloGene: 55565 ChEMBL: 5719 GeneCards: CDK8 Gene
EC number	2.7.11.22, 2.7.11.23
Gene ontology Molecular function • protein kinase activity • cyclin-dependent protein serine/threonine kinase activity • protein binding • ATP binding • RNA polymerase II carboxy-terminal domain kinase activity • ubiquitin protein ligase activity Cellular component • ubiquitin ligase complex • nucleus • nucleoplasm • mediator complex Biological process • transcription, DNA-templated • transcription initiation from RNA polymerase II promoter • protein phosphorylation • transforming growth factor beta receptor signaling pathway • Notch signaling pathway • gene expression • protein ubiquitination • positive regulation of transcription from RNA polymerase II promoter • regulation of cell cycle • negative regulation of triglyceride metabolic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1024	264064
Ensembl	ENSG00000132964	ENSMUSG00000029635
UniProt	P49336	Q8R3L8
RefSeq (mRNA)	NM_001260	NM_153599
RefSeq (protein)	NP_001251	NP_705827
Location (UCSC)	Chr 13: 26.25 – 26.41 Mb	Chr 5: 146.23 – 146.3 Mb
PubMed search

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

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.^[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

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

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

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

• CCNC,^{[1][15][16][17][18]}
• CREB binding protein,^[17]
• CRSP3,^[15][16]
• MED1,^[15][19]
• MED12,^[15][19]
• MED14,^[16][19]
• MED16,^[15][19]
• MED17,^[15][19]
• MED21,^{[15][17][19][20]}
• MED24,^[15][19]
• MED26,^[21]
• MED6,^{[15][16][19][22]}
• Notch proteins,^[5]
• POLR2A,^[17]
• SMARCB1,^[17]
• STAT1,^[7] and
• SREBP.^[6]

References

1. 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. 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. 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. 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. 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. 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. 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. 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. 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

• 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. 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. 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. 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. doi:10.1038/19783. PMID 10235266.
• Akoulitchev S, Chuikov S, Reinberg D (Sep 2000). "TFIIH is negatively regulated by cdk8-containing mediator complexes". Nature 407 (6800): 102–6. doi:10.1038/35024111. PMID 10993082.
• 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.
• 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 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". The Journal of Biological Chemistry 278 (17): 15123–7. doi:10.1074/jbc.C300054200. PMID 12584197.

External links

• CDK8 protein, human at the US 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.