Cyclin-dependent kinase 8: Difference between revisions

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{{Infobox_gene}}
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'''Cell division protein kinase 8''' is an [[enzyme]] that in humans is encoded by the ''CDK8'' [[gene]].<ref name="pmid7568034">{{cite journal | vauthors = Tassan JP, Jaquenoud M, Léopold P, Schultz SJ, Nigg EA | title = Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 19 | pages = 8871–5 | date = Sep 1995 | pmid = 7568034 | pmc = 41069 | doi = 10.1073/pnas.92.19.8871 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: CDK8 cyclin-dependent kinase 8| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1024| accessdate = }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Cyclin-dependent kinase 8
| HGNCid = 1779
| Symbol = CDK8
| AltSymbols =; K35; MGC126074; MGC126075
| OMIM = 603184
| ECnumber = 
| Homologene = 55565
| MGIid = 1196224
| GeneAtlas_image1 = PBB_GE_CDK8_204831_at_tn.png
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0004672 |text = protein kinase activity}} {{GNF_GO|id=GO:0004674 |text = protein serine/threonine kinase activity}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0016740 |text = transferase activity}}
| Component = {{GNF_GO|id=GO:0000119 |text = mediator complex}} {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0000074 |text = regulation of progression through cell cycle}} {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}} {{GNF_GO|id=GO:0007049 |text = cell cycle}} {{GNF_GO|id=GO:0051301 |text = cell division}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1024
    | Hs_Ensembl = ENSG00000132964
    | Hs_RefseqProtein = NP_001251
    | Hs_RefseqmRNA = NM_001260
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 13
    | Hs_GenLoc_start = 25726276
    | Hs_GenLoc_end = 25877375
    | Hs_Uniprot = P49336
    | Mm_EntrezGene = 264064
    | Mm_Ensembl = ENSMUSG00000029635
    | Mm_RefseqmRNA = NM_181570
    | Mm_RefseqProtein = NP_853548
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 5
    | Mm_GenLoc_start = 146535913
    | Mm_GenLoc_end = 146607053
    | Mm_Uniprot = 
  }}
}}
'''Cyclin-dependent kinase 8''', also known as '''CDK8''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: CDK8 cyclin-dependent kinase 8| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1024| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{PBB_Summary
| section_title =  
| summary_text = The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression. This kinase and its regulatory subunit cyclin C are components of the RNA polymerase II holoenzyme complex, which phosphorylates the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II. This kinase has also been shown to regulate transcription by targeting the CDK7/cyclin H subunits of the general transcription initiation factor IIH (TFIIH), thus providing a link between the 'Mediator-like' protein complexes and the basal transcription machinery.<ref name="entrez">{{cite web | title = Entrez Gene: CDK8 cyclin-dependent kinase 8| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1024| accessdate = }}</ref>
}}


==References==
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>
{{reflist|2}}
 
==Further reading==
== Clinical significance ==
{{refbegin | 2}}
 
{{PBB_Further_reading
CDK8 is a colorectal cancer [[oncogene]]: the ''CDK8'' gene is amplified in human colorectal tumors, activating [[Beta-catenin|β-catenin]]-mediated transcription that drives colon tumorigenesis.<ref>{{cite journal | vauthors = 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 | title = CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity | journal = Nature | volume = 455 | issue = 7212 | pages = 547–51 | date = Sep 2008 | pmid = 18794900 | doi = 10.1038/nature07179 | pmc=2587138}}</ref> However, CDK8 may not be oncogenic in all cell types, and indeed may act as a [[tumor suppressor gene|tumor suppressor]] in the [[Notch signaling pathway|notch]] and [[Epidermal growth factor receptor|EGFR signaling pathways]]. Specifically, CDK8 promotes [[Proteasome|turnover]] of the [[notch proteins|notch]] intracellular domain,<ref name="Fryer CJ 2004"/> and inhibits [[Epidermal growth factor receptor|EGFR signaling]]-driven cell fates in ''[[Caenorhabditis elegans|C. elegans]]''.<ref name="ReferenceB"/> Thus, ''CDK8'' may be an [[oncogene]] in cancers driven by [[Wnt signaling pathway|Wnt]]/[[Beta-catenin|β-catenin]] signaling, but could instead be a [[tumor suppressor gene]] in cancers driven by notch or [[Epidermal growth factor receptor|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 <ref>{{cite journal | vauthors = Donner AJ, Szostek S, Hoover JM, Espinosa JM | title = CDK8 is a stimulus-specific positive coregulator of p53 target genes | journal = Molecular Cell | volume = 27 | issue = 1 | pages = 121–33 | date = Jul 2007 | pmid = 17612495 | doi = 10.1016/j.molcel.2007.05.026 | pmc=2936241}}</ref> 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.
| citations =
 
*{{cite journal | author=Tassan JP, Jaquenoud M, Léopold P, ''et al.'' |title=Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 19 |pages= 8871-5 |year= 1995 |pmid= 7568034 |doi= }}
== As a potential drug target ==
*{{cite journal | author=Schultz SJ, Nigg EA |title=Identification of 21 novel human protein kinases, including 3 members of a family related to the cell cycle regulator nimA of Aspergillus nidulans. |journal=Cell Growth Differ. |volume=4 |issue= 10 |pages= 821-30 |year= 1994 |pmid= 8274451 |doi= }}
 
*{{cite journal | author=Rickert P, Seghezzi W, Shanahan F, ''et al.'' |title=Cyclin C/CDK8 is a novel CTD kinase associated with RNA polymerase II. |journal=Oncogene |volume=12 |issue= 12 |pages= 2631-40 |year= 1996 |pmid= 8700522 |doi= }}
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]].
*{{cite journal | author=Cujec TP, Cho H, Maldonado E, ''et al.'' |title=The human immunodeficiency virus transactivator Tat interacts with the RNA polymerase II holoenzyme. |journal=Mol. Cell. Biol. |volume=17 |issue= 4 |pages= 1817-23 |year= 1997 |pmid= 9121429 |doi= }}
 
*{{cite journal | author=Scully R, Anderson SF, Chao DM, ''et al.'' |title=BRCA1 is a component of the RNA polymerase II holoenzyme. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 11 |pages= 5605-10 |year= 1997 |pmid= 9159119 |doi= }}
== Interactions ==
*{{cite journal | author=Neish AS, Anderson SF, Schlegel BP, ''et al.'' |title=Factors associated with the mammalian RNA polymerase II holoenzyme. |journal=Nucleic Acids Res. |volume=26 |issue= 3 |pages= 847-53 |year= 1998 |pmid= 9443979 |doi= }}
 
*{{cite journal | author=Cho H, Orphanides G, Sun X, ''et al.'' |title=A human RNA polymerase II complex containing factors that modify chromatin structure. |journal=Mol. Cell. Biol. |volume=18 |issue= 9 |pages= 5355-63 |year= 1998 |pmid= 9710619 |doi= }}
Cyclin-dependent kinase 8 has been shown to [[Protein-protein interaction|interact]] with:
*{{cite journal | author=Sun X, Zhang Y, Cho H, ''et al.'' |title=NAT, a human complex containing Srb polypeptides that functions as a negative regulator of activated transcription. |journal=Mol. Cell |volume=2 |issue= 2 |pages= 213-22 |year= 1998 |pmid= 9734358 |doi= }}
{{div col|colwidth=20em}}
*{{cite journal | author=Rickert P, Corden JL, Lees E |title=Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases. |journal=Oncogene |volume=18 |issue= 4 |pages= 1093-102 |year= 1999 |pmid= 10023686 |doi= 10.1038/sj.onc.1202399 }}
* [[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>
*{{cite journal | author=Gu W, Malik S, Ito M, ''et al.'' |title=A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation. |journal=Mol. Cell |volume=3 |issue= 1 |pages= 97-108 |year= 1999 |pmid= 10024883 |doi=  }}
* [[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>
*{{cite journal  | author=Ito M, Yuan CX, Malik S, ''et al.'' |title=Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators. |journal=Mol. Cell |volume=3 |issue= 3 |pages= 361-70 |year= 1999 |pmid= 10198638 |doi= }}
* [[CRSP3]]<ref name = pmid11867769/><ref name = pmid11416138/>
*{{cite journal  | author=Rachez C, Lemon BD, Suldan Z, ''et al.'' |title=Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. |journal=Nature |volume=398 |issue= 6730 |pages= 824-8 |year= 1999 |pmid= 10235266 |doi= 10.1038/19783 }}
* [[MED1]]<ref name = pmid11867769/><ref name = pmid10198638/>
*{{cite journal | author=Akoulitchev S, Chuikov S, Reinberg D |title=TFIIH is negatively regulated by cdk8-containing mediator complexes. |journal=Nature |volume=407 |issue= 6800 |pages= 102-6 |year= 2000 |pmid= 10993082 |doi= 10.1038/35024111 }}
* [[MED12]]<ref name = pmid11867769/><ref name = pmid10198638/>
*{{cite journal  | author=Ramanathan Y, Rajpara SM, Reza SM, ''et al.'' |title=Three RNA polymerase II carboxyl-terminal domain kinases display distinct substrate preferences. |journal=J. Biol. Chem. |volume=276 |issue= 14 |pages= 10913-20 |year= 2001 |pmid= 11278802 |doi= 10.1074/jbc.M010975200 }}
* [[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/>
*{{cite journal | author=Wang G, Cantin GT, Stevens JL, Berk AJ |title=Characterization of mediator complexes from HeLa cell nuclear extract. |journal=Mol. Cell. Biol. |volume=21 |issue= 14 |pages= 4604-13 |year= 2001 |pmid= 11416138 |doi= 10.1128/MCB.21.14.4604-4613.2001 }}
* [[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>
*{{cite journal  | author=Di Pietro C, Rapisarda A, Bonaiuto C, ''et al.'' |title=Genomics of the human genes encoding four TAFII subunits of TFIID, the three subunits of TFIIA, as well as CDK8 and SURB7. |journal=Somat. Cell Mol. Genet. |volume=25 |issue= 3 |pages= 185-9 |year= 2001 |pmid= 11441538 |doi= }}
* [[MED17]]<ref name = pmid11867769/><ref name = pmid10198638/>
*{{cite journal | author=Vogel L, Baratte B, Détivaud L, ''et al.'' |title=Molecular cloning and characterisation of p15(CDK-BP), a novel CDK-binding protein. |journal=Biochim. Biophys. Acta |volume=1589 |issue= 2 |pages= 219-31 |year= 2002 |pmid= 12007796 |doi=  }}
* [[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>
*{{cite journal | author=Crowley TE, Kaine EM, Yoshida M, ''et al.'' |title=Reproductive cycle regulation of nuclear import, euchromatic localization, and association with components of Pol II mediator of a mammalian double-bromodomain protein. |journal=Mol. Endocrinol. |volume=16 |issue= 8 |pages= 1727-37 |year= 2003 |pmid= 12145330 |doi=  }}
* [[MED24]]<ref name = pmid11867769/><ref name = pmid10198638/>
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* [[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>
*{{cite journal | author=Sato S, Tomomori-Sato C, Banks CA, ''et al.'' |title=Identification of mammalian Mediator subunits with similarities to yeast Mediator subunits Srb5, Srb6, Med11, and Rox3. |journal=J. Biol. Chem. |volume=278 |issue= 17 |pages= 15123-7 |year= 2003 |pmid= 12584197 |doi= 10.1074/jbc.C300054200 }}
* [[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"/>
* [[POLR2A]]<ref name = pmid9710619/>
* [[SMARCB1]]<ref name = pmid9710619/>
* [[STAT1]]<ref name="Bancerek J 2012"/>
* [[Sterol regulatory element-binding protein|SREBP]]<ref name="ReferenceA"/>
{{Div col end}}
 
== References ==
{{reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Schultz SJ, Nigg EA | title = Identification of 21 novel human protein kinases, including 3 members of a family related to the cell cycle regulator nimA of Aspergillus nidulans | journal = Cell Growth & Differentiation | volume = 4 | issue = 10 | pages = 821–30 | date = Oct 1993 | pmid = 8274451 | doi =  }}
* {{cite journal | vauthors = Rickert P, Seghezzi W, Shanahan F, Cho H, Lees E | title = Cyclin C/CDK8 is a novel CTD kinase associated with RNA polymerase II | journal = Oncogene | volume = 12 | issue = 12 | pages = 2631–40 | date = Jun 1996 | pmid = 8700522 | doi =  }}
* {{cite journal | vauthors = Cujec TP, Cho H, Maldonado E, Meyer J, Reinberg D, Peterlin BM | title = The human immunodeficiency virus transactivator Tat interacts with the RNA polymerase II holoenzyme | journal = Molecular and Cellular Biology | volume = 17 | issue = 4 | pages = 1817–23 | date = Apr 1997 | pmid = 9121429 | pmc = 232028 | doi =  }}
* {{cite journal | vauthors = Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, Livingston DM, Parvin JD | title = BRCA1 is a component of the RNA polymerase II holoenzyme | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 11 | pages = 5605–10 | date = May 1997 | pmid = 9159119 | pmc = 20825 | doi = 10.1073/pnas.94.11.5605 }}
* {{cite journal | vauthors = Neish AS, Anderson SF, Schlegel BP, Wei W, Parvin JD | title = Factors associated with the mammalian RNA polymerase II holoenzyme | journal = Nucleic Acids Research | volume = 26 | issue = 3 | pages = 847–53 | date = Feb 1998 | pmid = 9443979 | pmc = 147327 | doi = 10.1093/nar/26.3.847 }}
* {{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 =  }}
* {{cite journal | vauthors = Sun X, Zhang Y, Cho H, Rickert P, Lees E, Lane W, Reinberg D | title = NAT, a human complex containing Srb polypeptides that functions as a negative regulator of activated transcription | journal = Molecular Cell | volume = 2 | issue = 2 | pages = 213–22 | date = Aug 1998 | pmid = 9734358 | doi = 10.1016/S1097-2765(00)80131-8 }}
* {{cite journal | vauthors = Rickert P, Corden JL, Lees E | title = Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases | journal = Oncogene | volume = 18 | issue = 4 | pages = 1093–102 | date = Jan 1999 | pmid = 10023686 | doi = 10.1038/sj.onc.1202399 }}
* {{cite journal | vauthors = Gu W, Malik S, Ito M, Yuan CX, Fondell JD, Zhang X, Martinez E, Qin J, Roeder RG | title = A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation | journal = Molecular Cell | volume = 3 | issue = 1 | pages = 97–108 | date = Jan 1999 | pmid = 10024883 | doi = 10.1016/S1097-2765(00)80178-1 }}
* {{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 }}
* {{cite journal | vauthors = Rachez C, Lemon BD, Suldan Z, Bromleigh V, Gamble M, Näär AM, Erdjument-Bromage H, Tempst P, Freedman LP | title = Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex | journal = Nature | volume = 398 | issue = 6730 | pages = 824–8 | date = Apr 1999 | pmid = 10235266 | doi = 10.1038/19783 }}
* {{cite journal | vauthors = Akoulitchev S, Chuikov S, Reinberg D | title = TFIIH is negatively regulated by cdk8-containing mediator complexes | journal = Nature | volume = 407 | issue = 6800 | pages = 102–6 | date = Sep 2000 | pmid = 10993082 | doi = 10.1038/35024111 }}
* {{cite journal | vauthors = Ramanathan Y, Rajpara SM, Reza SM, Lees E, Shuman S, Mathews MB, Pe'ery T | title = Three RNA polymerase II carboxyl-terminal domain kinases display distinct substrate preferences | journal = The Journal of Biological Chemistry | volume = 276 | issue = 14 | pages = 10913–20 | date = Apr 2001 | pmid = 11278802 | doi = 10.1074/jbc.M010975200 }}
* {{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 }}
* {{cite journal | vauthors = Di Pietro C, Rapisarda A, Bonaiuto C, Lizzio MN, Engel H, Amico V, Scalia M, Amato A, Grzeschik KH, Sichel G, Purrello M | title = Genomics of the human genes encoding four TAFII subunits of TFIID, the three subunits of TFIIA, as well as CDK8 and SURB7 | journal = Somatic Cell and Molecular Genetics | volume = 25 | issue = 3 | pages = 185–9 | date = May 1999 | pmid = 11441538 | doi = 10.1023/A:1018897624615 }}
* {{cite journal | vauthors = Vogel L, Baratte B, Détivaud L, Azzi L, Leopold P, Meijer L | title = Molecular cloning and characterisation of p15(CDK-BP), a novel CDK-binding protein | journal = Biochimica et Biophysica Acta | volume = 1589 | issue = 2 | pages = 219–31 | date = Apr 2002 | pmid = 12007796 | doi = 10.1016/S0167-4889(02)00175-1 }}
* {{cite journal | vauthors = Crowley TE, Kaine EM, Yoshida M, Nandi A, Wolgemuth DJ | title = Reproductive cycle regulation of nuclear import, euchromatic localization, and association with components of Pol II mediator of a mammalian double-bromodomain protein | journal = Molecular Endocrinology | volume = 16 | issue = 8 | pages = 1727–37 | date = Aug 2002 | pmid = 12145330 | doi = 10.1210/me.2001-0353 }}
* {{cite journal | vauthors = 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 | title = Identification of mammalian Mediator subunits with similarities to yeast Mediator subunits Srb5, Srb6, Med11, and Rox3 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 17 | pages = 15123–7 | date = Apr 2003 | pmid = 12584197 | doi = 10.1074/jbc.C300054200 }}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{MeshName|CDK8+protein,+human}}
* {{MeshName|CDK8+protein,+human}}
* {{UCSC genome browser|CDK8}}
* {{UCSC gene details|CDK8}}


{{Enzyme-stub}}
{{Cell cycle proteins}}
{{Cell cycle proteins}}
{{Serine/threonine-specific protein kinases}}
{{Enzymes}}
{{Portal bar|Molecular and Cellular Biology|border=no}}


{{DEFAULTSORT:Cyclin-dependent kinase 08}}
[[Category:Cell cycle]]
[[Category:Cell cycle]]
[[Category:Proteins]]
[[Category:EC 2.7.11]]

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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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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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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