Cyclin-dependent kinase 8 explained

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.

An autosomal dominant syndrome has been described that is associated with mutations in the ATP binding pocket of the kinase domain.^[14] 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.^[15] 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] [16]}
• CREB binding protein^[17]
• CRSP3
  • • MED1 MED12 MED14^[18]
• MED16^{[19] [20]}
• MED17^{[19] [20]}
• MED21^{[19] [17] [20] [21]}
• MED24^{[19] [20]}
• MED26^[22]
• MED6^{[19] [18] [20] [23]}
• Notch proteins^[5]
• POLR2A^[17]
• SMARCB1^[17]
• STAT1^[7]
• SREBP^[6]

Further reading

• Schultz SJ, Nigg EA . 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 . Oct 1993 . 8274451 .
• Rickert P, Seghezzi W, Shanahan F, Cho H, Lees E . Cyclin C/CDK8 is a novel CTD kinase associated with RNA polymerase II . Oncogene . 12 . 12 . 2631–40 . Jun 1996 . 8700522 .
• Cujec TP, Cho H, Maldonado E, Meyer J, Reinberg D, Peterlin BM . The human immunodeficiency virus transactivator Tat interacts with the RNA polymerase II holoenzyme . Molecular and Cellular Biology . 17 . 4 . 1817–23 . Apr 1997 . 9121429 . 232028 . 10.1128/MCB.17.4.1817.
• Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, Livingston DM, Parvin JD . 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 . May 1997 . 9159119 . 20825 . 10.1073/pnas.94.11.5605 . 1997PNAS...94.5605S . free .
• Neish AS, Anderson SF, Schlegel BP, Wei W, Parvin JD . Factors associated with the mammalian RNA polymerase II holoenzyme . Nucleic Acids Research . 26 . 3 . 847–53 . Feb 1998 . 9443979 . 147327 . 10.1093/nar/26.3.847 .
• Cho H, Orphanides G, Sun X, Yang XJ, Ogryzko V, Lees E, Nakatani Y, Reinberg D . A human RNA polymerase II complex containing factors that modify chromatin structure . Molecular and Cellular Biology . 18 . 9 . 5355–63 . Sep 1998 . 9710619 . 109120 . 10.1128/MCB.18.9.5355.
• Sun X, Zhang Y, Cho H, Rickert P, Lees E, Lane W, Reinberg D . NAT, a human complex containing Srb polypeptides that functions as a negative regulator of activated transcription . Molecular Cell . 2 . 2 . 213–22 . Aug 1998 . 9734358 . 10.1016/S1097-2765(00)80131-8 . free .
• Rickert P, Corden JL, Lees E . Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases . Oncogene . 18 . 4 . 1093–102 . Jan 1999 . 10023686 . 10.1038/sj.onc.1202399 . free .
• Gu W, Malik S, Ito M, Yuan CX, Fondell JD, Zhang X, Martinez E, Qin J, Roeder RG . A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation . Molecular Cell . 3 . 1 . 97–108 . Jan 1999 . 10024883 . 10.1016/S1097-2765(00)80178-1 . free .
• Ito M, Yuan CX, Malik S, Gu W, Fondell JD, Yamamura S, Fu ZY, Zhang X, Qin J, Roeder RG . 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 . Mar 1999 . 10198638 . 10.1016/S1097-2765(00)80463-3 . free .
• Rachez C, Lemon BD, Suldan Z, Bromleigh V, Gamble M, Näär AM, Erdjument-Bromage H, Tempst P, Freedman LP . Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex . Nature . 398 . 6730 . 824–8 . Apr 1999 . 10235266 . 10.1038/19783 . 1999Natur.398..824R . 204992765 .
• Akoulitchev S, Chuikov S, Reinberg D . TFIIH is negatively regulated by cdk8-containing mediator complexes . Nature . 407 . 6800 . 102–6 . Sep 2000 . 10993082 . 10.1038/35024111 . 2000Natur.407..102A . 4430185 .
• Ramanathan Y, Rajpara SM, Reza SM, Lees E, Shuman S, Mathews MB, Pe'ery T . Three RNA polymerase II carboxyl-terminal domain kinases display distinct substrate preferences . The Journal of Biological Chemistry . 276 . 14 . 10913–20 . Apr 2001 . 11278802 . 10.1074/jbc.M010975200 . free .
• Wang G, Cantin GT, Stevens JL, Berk AJ . Characterization of mediator complexes from HeLa cell nuclear extract . Molecular and Cellular Biology . 21 . 14 . 4604–13 . Jul 2001 . 11416138 . 87123 . 10.1128/MCB.21.14.4604-4613.2001 .
• Di Pietro C, Rapisarda A, Bonaiuto C, Lizzio MN, Engel H, Amico V, Scalia M, Amato A, Grzeschik KH, Sichel G, Purrello M . 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 . May 1999 . 11441538 . 10.1023/A:1018897624615 . 42316067 .
• Vogel L, Baratte B, Détivaud L, Azzi L, Leopold P, Meijer L . 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 . Apr 2002 . 12007796 . 10.1016/S0167-4889(02)00175-1 . free .
• Crowley TE, Kaine EM, Yoshida M, Nandi A, Wolgemuth DJ . 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 . Aug 2002 . 12145330 . 10.1210/me.2001-0353 . free .
• 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 . 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 . Apr 2003 . 12584197 . 10.1074/jbc.C300054200 . 41400940 . free .

Notes and References

1. Tassan JP, Jaquenoud M, Léopold P, Schultz SJ, Nigg EA . 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 . Sep 1995 . 7568034 . 41069 . 10.1073/pnas.92.19.8871 . 1995PNAS...92.8871T . free .
2. Web site: Entrez Gene: CDK8 cyclin-dependent kinase 8.
3. Nemet J, Jelicic B, Rubelj I, Sopta M . The two faces of Cdk8, a positive/negative regulator of transcription . Biochimie . 97 . 22–7 . Feb 2014 . 24139904 . 10.1016/j.biochi.2013.10.004 .
4. Poss ZC, Ebmeier CC, Taatjes DJ . The mediator complex and transcription regulation . Critical Reviews in Biochemistry and Molecular Biology . 48 . 6 . 575–608 . 24088064 . 10.3109/10409238.2013.840259 . 3852498. 2013 .
5. Fryer CJ, White JB, Jones KA . Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover . Molecular Cell . 16 . 4 . 509–20 . Nov 2004 . 15546612 . 10.1016/j.molcel.2004.10.014 . free .
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 . Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1 . The Journal of Clinical Investigation . 122 . 7 . 2417–27 . Jul 2012 . 22684109 . 10.1172/JCI61462 . 3386818.
7. Bancerek J, Poss ZC, Steinparzer I, Sedlyarov V, Pfaffenwimmer T, Mikulic I, Dölken L, Strobl B, Müller M, Taatjes DJ, Kovarik P . CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response . en . Immunity . 38 . 2 . 250–62 . Feb 2013 . 23352233 . 3580287 . 10.1016/j.immuni.2012.10.017 .
8. Gonzalez D, Hamidi N, Del Sol R, Benschop JJ, Nancy T, Li C, Francis L, Tzouros M, Krijgsveld J, Holstege FC, Conlan RS . 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 . Feb 2014 . 24550274 . 10.1073/pnas.1307525111 . 3932902. 2014PNAS..111.2500G . free .
9. Grants JM, Ying LT, Yoda A, You CC, Okano H, Sawa H, Taubert S . The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans . Genetics . 202 . 2 . 583–99 . Feb 2016 . 26715664 . 10.1534/genetics.115.180265 . 4788237 .
10. Taatjes DJ, Näär AM, Andel F, Nogales E, Tjian R . Structure, function, and activator-induced conformations of the CRSP coactivator . Science . 295 . 5557 . 1058–62 . Feb 2002 . 11834832 . 10.1126/science.1065249 . 2002Sci...295.1058T . 23446878 .
11. Tsai KL, Sato S, Tomomori-Sato C, Conaway RC, Conaway JW, Asturias FJ . A conserved Mediator-CDK8 kinase module association regulates Mediator-RNA polymerase II interaction . Nature Structural & Molecular Biology . 20 . 5 . 611–9 . May 2013 . 23563140 . 10.1038/nsmb.2549 . 3648612.
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 . CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity . Nature . 455 . 7212 . 547–51 . Sep 2008 . 18794900 . 10.1038/nature07179 . 2587138. 2008Natur.455..547F .
13. Donner AJ, Szostek S, Hoover JM, Espinosa JM . CDK8 is a stimulus-specific positive coregulator of p53 target genes . Molecular Cell . 27 . 1 . 121–33 . Jul 2007 . 17612495 . 10.1016/j.molcel.2007.05.026 . 2936241.
14. 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
15. 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 . Mediator kinase inhibition further activates super-enhancer-associated genes in AML . Nature . 526 . 7572 . 273–6 . Oct 2015 . 26416749 . 10.1038/nature14904 . 4641525 . 2015Natur.526..273P .
16. Zhang Y, Iratni R, Erdjument-Bromage H, Tempst P, Reinberg D . Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex . Cell . 89 . 3 . 357–64 . May 1997 . 9150135 . 10.1016/s0092-8674(00)80216-0. free .
17. Cho H, Orphanides G, Sun X, Yang XJ, Ogryzko V, Lees E, Nakatani Y, Reinberg D . A human RNA polymerase II complex containing factors that modify chromatin structure . Molecular and Cellular Biology . 18 . 9 . 5355–63 . Sep 1998 . 9710619 . 109120 . 10.1128/MCB.18.9.5355.
18. Wang G, Cantin GT, Stevens JL, Berk AJ . Characterization of mediator complexes from HeLa cell nuclear extract . Molecular and Cellular Biology . 21 . 14 . 4604–13 . Jul 2001 . 11416138 . 87123 . 10.1128/MCB.21.14.4604-4613.2001 .
19. Kang YK, Guermah M, Yuan CX, Roeder RG . 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 . Mar 2002 . 11867769 . 122401 . 10.1073/pnas.261715899 . 2002PNAS...99.2642K . free .
20. Ito M, Yuan CX, Malik S, Gu W, Fondell JD, Yamamura S, Fu ZY, Zhang X, Qin J, Roeder RG . 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 . Mar 1999 . 10198638 . 10.1016/s1097-2765(00)80463-3. free .
21. Suñé C, Hayashi T, Liu Y, Lane WS, Young RA, Garcia-Blanco MA . 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 . Oct 1997 . 9315662 . 232452 . 10.1128/MCB.17.10.6029.
22. 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 . A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology . Molecular Cell . 14 . 5 . 685–91 . Jun 2004 . 15175163 . 10.1016/j.molcel.2004.05.006 . free .
23. Yang F, DeBeaumont R, Zhou S, Näär AM . 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 . Feb 2004 . 14983011 . 356952 . 10.1073/pnas.0308676100. 2004PNAS..101.2339Y . free .