Cyclin-dependent kinase 8: Difference between revisions

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== Function ==
== 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 (coactivator)|mediator complex]] and regulate [[transcription (genetics)|transcription]] by several mechanisms. CDK8 binds to and/or phosphorylates several [[transcription factor]]s, which can have an activating or inhibitory effect on transcription factor function.<ref>{{cite journal | vauthors = Nemet J, Jelicic B, Rubelj I, Sopta M | title = The two faces of Cdk8, a positive/negative regulator of transcription | journal = Biochimie | volume = 97 | pages = 22–7 | date = Feb 2014 | pmid = 24139904 | doi = 10.1016/j.biochi.2013.10.004 }}</ref><ref>{{cite journal | vauthors = Poss ZC, Ebmeier CC, Taatjes DJ | title = The mediator complex and transcription regulation | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 48 | issue = 6 | pages = 575–608 | pmid = 24088064 | doi = 10.3109/10409238.2013.840259 | pmc=3852498}}</ref> CDK8 phosphorylates the [[Notch signaling pathway|Notch]] intracellular domain,<ref name="Fryer CJ 2004">{{cite journal | vauthors = Fryer CJ, White JB, Jones KA | title = Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover | journal = Molecular Cell | volume = 16 | issue = 4 | pages = 509–20 | date = Nov 2004 | pmid = 15546612 | doi = 10.1016/j.molcel.2004.10.014 }}</ref> [[Sterol regulatory element-binding protein|SREBP]],<ref name="ReferenceA">{{cite journal | vauthors = 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 | title = Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1 | journal = The Journal of Clinical Investigation | volume = 122 | issue = 7 | pages = 2417–27 | date = Jul 2012 | pmid = 22684109 | doi = 10.1172/JCI61462 | pmc=3386818}}</ref> and [[STAT1]] S727.<ref name="Bancerek J 2012">{{cite journal | vauthors = Bancerek J, Poss ZC, Steinparzer I, Sedlyarov V, Pfaffenwimmer T, Mikulic I, Dölken L, Strobl B, Müller M, Taatjes DJ, Kovarik P | title = CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response | language = English | journal = Immunity | volume = 38 | issue = 2 | pages = 250–62 | date = Feb 2013 | pmid = 23352233 | pmc = 3580287 | doi = 10.1016/j.immuni.2012.10.017 }}</ref> CDK8 also inhibits transcriptional activation by influencing [[Proteasome|turnover]] of subunits in the mediator complex tail module.<ref>{{cite journal | vauthors = Gonzalez D, Hamidi N, Del Sol R, Benschop JJ, Nancy T, Li C, Francis L, Tzouros M, Krijgsveld J, Holstege FC, Conlan RS | title = Suppression of Mediator is regulated by Cdk8-dependent Grr1 turnover of the Med3 coactivator | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 7 | pages = 2500–5 | date = Feb 2014 | pmid = 24550274 | doi = 10.1073/pnas.1307525111 | pmc=3932902}}</ref><ref name="ReferenceB">{{cite journal | vauthors = Grants JM, Ying LT, Yoda A, You CC, Okano H, Sawa H, Taubert S | title = The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans | journal = Genetics | volume = 202 | issue = 2 | pages = 583–99 | date = Feb 2016 | pmid = 26715664 | doi = 10.1534/genetics.115.180265 }}</ref> In addition, CDK8 influences binding of [[RNA polymerase II]] to the mediator complex.<ref>{{cite journal | vauthors = Taatjes DJ, Näär AM, Andel F, Nogales E, Tjian R | title = Structure, function, and activator-induced conformations of the CRSP coactivator | journal = Science | volume = 295 | issue = 5557 | pages = 1058–62 | date = Feb 2002 | pmid = 11834832 | doi = 10.1126/science.1065249 }}</ref><ref>{{cite journal | vauthors = Tsai KL, Sato S, Tomomori-Sato C, Conaway RC, Conaway JW, Asturias FJ | title = A conserved Mediator-CDK8 kinase module association regulates Mediator-RNA polymerase II interaction | journal = Nature Structural & Molecular Biology | volume = 20 | issue = 5 | pages = 611–9 | date = May 2013 | pmid = 23563140 | doi = 10.1038/nsmb.2549 | pmc=3648612}}</ref>
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 (coactivator)|mediator complex]] and regulate [[transcription (genetics)|transcription]] by several mechanisms. CDK8 binds to and/or phosphorylates several [[transcription factor]]s, which can have an activating or inhibitory effect on transcription factor function.<ref>{{cite journal | vauthors = Nemet J, Jelicic B, Rubelj I, Sopta M | title = The two faces of Cdk8, a positive/negative regulator of transcription | journal = Biochimie | volume = 97 | pages = 22–7 | date = Feb 2014 | pmid = 24139904 | doi = 10.1016/j.biochi.2013.10.004 }}</ref><ref>{{cite journal | vauthors = Poss ZC, Ebmeier CC, Taatjes DJ | title = The mediator complex and transcription regulation | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 48 | issue = 6 | pages = 575–608 | pmid = 24088064 | doi = 10.3109/10409238.2013.840259 | pmc=3852498}}</ref> CDK8 phosphorylates the [[Notch signaling pathway|Notch]] intracellular domain,<ref name="Fryer CJ 2004">{{cite journal | vauthors = Fryer CJ, White JB, Jones KA | title = Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover | journal = Molecular Cell | volume = 16 | issue = 4 | pages = 509–20 | date = Nov 2004 | pmid = 15546612 | doi = 10.1016/j.molcel.2004.10.014 }}</ref> [[Sterol regulatory element-binding protein|SREBP]],<ref name="ReferenceA">{{cite journal | vauthors = 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 | title = Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1 | journal = The Journal of Clinical Investigation | volume = 122 | issue = 7 | pages = 2417–27 | date = Jul 2012 | pmid = 22684109 | doi = 10.1172/JCI61462 | pmc=3386818}}</ref> and [[STAT1]] S727.<ref name="Bancerek J 2012">{{cite journal | vauthors = Bancerek J, Poss ZC, Steinparzer I, Sedlyarov V, Pfaffenwimmer T, Mikulic I, Dölken L, Strobl B, Müller M, Taatjes DJ, Kovarik P | title = CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response | language = English | journal = Immunity | volume = 38 | issue = 2 | pages = 250–62 | date = Feb 2013 | pmid = 23352233 | pmc = 3580287 | doi = 10.1016/j.immuni.2012.10.017 }}</ref> CDK8 also inhibits transcriptional activation by influencing [[Proteasome|turnover]] of subunits in the mediator complex tail module.<ref>{{cite journal | vauthors = Gonzalez D, Hamidi N, Del Sol R, Benschop JJ, Nancy T, Li C, Francis L, Tzouros M, Krijgsveld J, Holstege FC, Conlan RS | title = Suppression of Mediator is regulated by Cdk8-dependent Grr1 turnover of the Med3 coactivator | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 7 | pages = 2500–5 | date = Feb 2014 | pmid = 24550274 | doi = 10.1073/pnas.1307525111 | pmc=3932902}}</ref><ref name="ReferenceB">{{cite journal | vauthors = Grants JM, Ying LT, Yoda A, You CC, Okano H, Sawa H, Taubert S | title = The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans | journal = Genetics | volume = 202 | issue = 2 | pages = 583–99 | date = Feb 2016 | pmid = 26715664 | doi = 10.1534/genetics.115.180265 | pmc = 4788237 }}</ref> In addition, CDK8 influences binding of [[RNA polymerase II]] to the mediator complex.<ref>{{cite journal | vauthors = Taatjes DJ, Näär AM, Andel F, Nogales E, Tjian R | title = Structure, function, and activator-induced conformations of the CRSP coactivator | journal = Science | volume = 295 | issue = 5557 | pages = 1058–62 | date = Feb 2002 | pmid = 11834832 | doi = 10.1126/science.1065249 }}</ref><ref>{{cite journal | vauthors = Tsai KL, Sato S, Tomomori-Sato C, Conaway RC, Conaway JW, Asturias FJ | title = A conserved Mediator-CDK8 kinase module association regulates Mediator-RNA polymerase II interaction | journal = Nature Structural & Molecular Biology | volume = 20 | issue = 5 | pages = 611–9 | date = May 2013 | pmid = 23563140 | doi = 10.1038/nsmb.2549 | pmc=3648612}}</ref>


==  Clinical significance ==
==  Clinical significance ==
Line 12: Line 12:
== As a potential drug target ==
== As a potential drug target ==


The natural product [[cortistatins|cortistatin A]] is a potent and selective inhibitor of CDK8 and [[CDK19]].<ref>{{cite journal | vauthors = 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 | title = Mediator kinase inhibition further activates super-enhancer-associated genes in AML | journal = Nature | volume = 526 | issue = 7572 | pages = 273–6 | date = Oct 2015 | pmid = 26416749 | doi = 10.1038/nature14904 }}</ref> Inhibition of CDK8 and CDK19 with cortistatin A suppresses [[acute myeloid leukemia|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]].
The natural product [[cortistatins|cortistatin A]] is a potent and selective inhibitor of CDK8 and [[CDK19]].<ref>{{cite journal | vauthors = 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 | title = Mediator kinase inhibition further activates super-enhancer-associated genes in AML | journal = Nature | volume = 526 | issue = 7572 | pages = 273–6 | date = Oct 2015 | pmid = 26416749 | doi = 10.1038/nature14904 | pmc = 4641525 }}</ref> Inhibition of CDK8 and CDK19 with cortistatin A suppresses [[acute myeloid leukemia|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 ==
== Interactions ==
Line 18: Line 18:
Cyclin-dependent kinase 8 has been shown to [[Protein-protein interaction|interact]] with:
Cyclin-dependent kinase 8 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
{{div col|colwidth=20em}}
* [[CCNC (gene)|CCNC]],<ref name = pmid7568034/><ref name = pmid11867769/><ref name = pmid11416138/><ref name = pmid9710619/><ref name = pmid9150135>{{cite journal | vauthors = Zhang Y, Iratni R, Erdjument-Bromage H, Tempst P, Reinberg D | title = Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex | journal = Cell | volume = 89 | issue = 3 | pages = 357–64 | date = May 1997 | pmid = 9150135 | doi =  10.1016/s0092-8674(00)80216-0}}</ref>  
* [[CCNC (gene)|CCNC]]<ref name = pmid7568034/><ref name = pmid11867769/><ref name = pmid11416138/><ref name = pmid9710619/><ref name = pmid9150135>{{cite journal | vauthors = Zhang Y, Iratni R, Erdjument-Bromage H, Tempst P, Reinberg D | title = Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex | journal = Cell | volume = 89 | issue = 3 | pages = 357–64 | date = May 1997 | pmid = 9150135 | doi =  10.1016/s0092-8674(00)80216-0}}</ref>  
* [[CREB binding protein]],<ref name = pmid9710619>{{cite journal | vauthors = Cho H, Orphanides G, Sun X, Yang XJ, Ogryzko V, Lees E, Nakatani Y, Reinberg D | title = A human RNA polymerase II complex containing factors that modify chromatin structure | journal = Molecular and Cellular Biology | volume = 18 | issue = 9 | pages = 5355–63 | date = Sep 1998 | pmid = 9710619 | pmc = 109120 | doi =  }}</ref>  
* [[CREB binding protein]]<ref name = pmid9710619>{{cite journal | vauthors = Cho H, Orphanides G, Sun X, Yang XJ, Ogryzko V, Lees E, Nakatani Y, Reinberg D | title = A human RNA polymerase II complex containing factors that modify chromatin structure | journal = Molecular and Cellular Biology | volume = 18 | issue = 9 | pages = 5355–63 | date = Sep 1998 | pmid = 9710619 | pmc = 109120 | doi =  }}</ref>  
* [[CRSP3]],<ref name = pmid11867769/><ref name = pmid11416138/>
* [[CRSP3]]<ref name = pmid11867769/><ref name = pmid11416138/>
* [[MED1]],<ref name = pmid11867769/><ref name = pmid10198638/>  
* [[MED1]]<ref name = pmid11867769/><ref name = pmid10198638/>  
* [[MED12]],<ref name = pmid11867769/><ref name = pmid10198638/>  
* [[MED12]]<ref name = pmid11867769/><ref name = pmid10198638/>  
* [[MED14]],<ref name = pmid11416138>{{cite journal | vauthors = Wang G, Cantin GT, Stevens JL, Berk AJ | title = Characterization of mediator complexes from HeLa cell nuclear extract | journal = Molecular and Cellular Biology | volume = 21 | issue = 14 | pages = 4604–13 | date = Jul 2001 | pmid = 11416138 | pmc = 87123 | doi = 10.1128/MCB.21.14.4604-4613.2001 }}</ref><ref name = pmid10198638/>  
* [[MED14]]<ref name = pmid11416138>{{cite journal | vauthors = Wang G, Cantin GT, Stevens JL, Berk AJ | title = Characterization of mediator complexes from HeLa cell nuclear extract | journal = Molecular and Cellular Biology | volume = 21 | issue = 14 | pages = 4604–13 | date = Jul 2001 | pmid = 11416138 | pmc = 87123 | doi = 10.1128/MCB.21.14.4604-4613.2001 }}</ref><ref name = pmid10198638/>  
* [[MED16]],<ref name = pmid11867769>{{cite journal | vauthors = Kang YK, Guermah M, Yuan CX, Roeder RG | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 5 | pages = 2642–7 | date = Mar 2002 | pmid = 11867769 | pmc = 122401 | doi = 10.1073/pnas.261715899 }}</ref><ref name = pmid10198638>{{cite journal | vauthors = Ito M, Yuan CX, Malik S, Gu W, Fondell JD, Yamamura S, Fu ZY, Zhang X, Qin J, Roeder RG | title = Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators | journal = Molecular Cell | volume = 3 | issue = 3 | pages = 361–70 | date = Mar 1999 | pmid = 10198638 | doi =  10.1016/s1097-2765(00)80463-3}}</ref>  
* [[MED16]]<ref name = pmid11867769>{{cite journal | vauthors = Kang YK, Guermah M, Yuan CX, Roeder RG | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 5 | pages = 2642–7 | date = Mar 2002 | pmid = 11867769 | pmc = 122401 | doi = 10.1073/pnas.261715899 }}</ref><ref name = pmid10198638>{{cite journal | vauthors = Ito M, Yuan CX, Malik S, Gu W, Fondell JD, Yamamura S, Fu ZY, Zhang X, Qin J, Roeder RG | title = Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators | journal = Molecular Cell | volume = 3 | issue = 3 | pages = 361–70 | date = Mar 1999 | pmid = 10198638 | doi =  10.1016/s1097-2765(00)80463-3}}</ref>  
* [[MED17]],<ref name = pmid11867769/><ref name = pmid10198638/>  
* [[MED17]]<ref name = pmid11867769/><ref name = pmid10198638/>  
* [[MED21]],<ref name = pmid11867769/><ref name = pmid9710619/><ref name = pmid10198638/><ref name = pmid9315662>{{cite journal | vauthors = Suñé C, Hayashi T, Liu Y, Lane WS, Young RA, Garcia-Blanco MA | title = CA150, a nuclear protein associated with the RNA polymerase II holoenzyme, is involved in Tat-activated human immunodeficiency virus type 1 transcription | journal = Molecular and Cellular Biology | volume = 17 | issue = 10 | pages = 6029–39 | date = Oct 1997 | pmid = 9315662 | pmc = 232452 | doi =  }}</ref>  
* [[MED21]]<ref name = pmid11867769/><ref name = pmid9710619/><ref name = pmid10198638/><ref name = pmid9315662>{{cite journal | vauthors = Suñé C, Hayashi T, Liu Y, Lane WS, Young RA, Garcia-Blanco MA | title = CA150, a nuclear protein associated with the RNA polymerase II holoenzyme, is involved in Tat-activated human immunodeficiency virus type 1 transcription | journal = Molecular and Cellular Biology | volume = 17 | issue = 10 | pages = 6029–39 | date = Oct 1997 | pmid = 9315662 | pmc = 232452 | doi =  }}</ref>  
* [[MED24]],<ref name = pmid11867769/><ref name = pmid10198638/>  
* [[MED24]]<ref name = pmid11867769/><ref name = pmid10198638/>  
* [[MED26]],<ref name = pmid15175163>{{cite journal | vauthors = 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 | title = A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology | journal = Molecular Cell | volume = 14 | issue = 5 | pages = 685–91 | date = Jun 2004 | pmid = 15175163 | doi = 10.1016/j.molcel.2004.05.006 }}</ref>  
* [[MED26]]<ref name = pmid15175163>{{cite journal | vauthors = 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 | title = A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology | journal = Molecular Cell | volume = 14 | issue = 5 | pages = 685–91 | date = Jun 2004 | pmid = 15175163 | doi = 10.1016/j.molcel.2004.05.006 }}</ref>  
* [[MED6]],<ref name = pmid11867769/><ref name = pmid11416138/><ref name = pmid10198638/><ref name = pmid14983011>{{cite journal | vauthors = Yang F, DeBeaumont R, Zhou S, Näär AM | title = The activator-recruited cofactor/Mediator coactivator subunit ARC92 is a functionally important target of the VP16 transcriptional activator | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 8 | pages = 2339–44 | date = Feb 2004 | pmid = 14983011 | pmc = 356952 | doi =  10.1073/pnas.0308676100}}</ref>  
* [[MED6]]<ref name = pmid11867769/><ref name = pmid11416138/><ref name = pmid10198638/><ref name = pmid14983011>{{cite journal | vauthors = Yang F, DeBeaumont R, Zhou S, Näär AM | title = The activator-recruited cofactor/Mediator coactivator subunit ARC92 is a functionally important target of the VP16 transcriptional activator | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 8 | pages = 2339–44 | date = Feb 2004 | pmid = 14983011 | pmc = 356952 | doi =  10.1073/pnas.0308676100}}</ref>  
* [[Notch proteins]],<ref name="Fryer CJ 2004"/>
* [[Notch proteins]]<ref name="Fryer CJ 2004"/>
* [[POLR2A]],<ref name = pmid9710619/>
* [[POLR2A]]<ref name = pmid9710619/>
* [[SMARCB1]],<ref name = pmid9710619/>  
* [[SMARCB1]]<ref name = pmid9710619/>  
* [[STAT1]],<ref name="Bancerek J 2012"/> and
* [[STAT1]]<ref name="Bancerek J 2012"/>
* [[Sterol regulatory element-binding protein|SREBP]].<ref name="ReferenceA"/>
* [[Sterol regulatory element-binding protein|SREBP]]<ref name="ReferenceA"/>
{{Div col end}}
{{Div col end}}


Latest revision as of 11:30, 9 January 2019

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

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:

References

  1. ↑ 1.0 1.1 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. ↑ 5.0 5.1 5.2 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. ↑ 6.0 6.1 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. ↑ 7.0 7.1 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. ↑ 9.0 9.1 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.
  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. PMC 4641525. PMID 26416749.
  15. ↑ 15.0 15.1 15.2 15.3 15.4 15.5 15.6 15.7 15.8 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. ↑ 16.0 16.1 16.2 16.3 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. ↑ 17.0 17.1 17.2 17.3 17.4 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. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 19.6 19.7 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

External links

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