Biology:Cyclin-dependent kinase 8

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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:


References

  1. ↑ 1.0 1.1 "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. doi:10.1073/pnas.92.19.8871. PMID 7568034. Bibcode: 1995PNAS...92.8871T. 
  2. ↑ "Entrez Gene: CDK8 cyclin-dependent kinase 8". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1024. 
  3. ↑ "The two faces of Cdk8, a positive/negative regulator of transcription". Biochimie 97: 22–7. Feb 2014. doi:10.1016/j.biochi.2013.10.004. PMID 24139904. 
  4. ↑ "The mediator complex and transcription regulation". Critical Reviews in Biochemistry and Molecular Biology 48 (6): 575–608. 2013. doi:10.3109/10409238.2013.840259. PMID 24088064. 
  5. ↑ 5.0 5.1 5.2 "Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover". Molecular Cell 16 (4): 509–20. Nov 2004. doi:10.1016/j.molcel.2004.10.014. PMID 15546612. 
  6. ↑ 6.0 6.1 "Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1". The Journal of Clinical Investigation 122 (7): 2417–27. Jul 2012. doi:10.1172/JCI61462. PMID 22684109. 
  7. ↑ 7.0 7.1 "CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response" (in en). Immunity 38 (2): 250–62. Feb 2013. doi:10.1016/j.immuni.2012.10.017. PMID 23352233. 
  8. ↑ "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. doi:10.1073/pnas.1307525111. PMID 24550274. Bibcode: 2014PNAS..111.2500G. 
  9. ↑ 9.0 9.1 "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. doi:10.1534/genetics.115.180265. PMID 26715664. 
  10. ↑ "Structure, function, and activator-induced conformations of the CRSP coactivator". Science 295 (5557): 1058–62. Feb 2002. doi:10.1126/science.1065249. PMID 11834832. Bibcode: 2002Sci...295.1058T. 
  11. ↑ "A conserved Mediator-CDK8 kinase module association regulates Mediator-RNA polymerase II interaction". Nature Structural & Molecular Biology 20 (5): 611–9. May 2013. doi:10.1038/nsmb.2549. PMID 23563140. 
  12. ↑ "CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity". Nature 455 (7212): 547–51. Sep 2008. doi:10.1038/nature07179. PMID 18794900. Bibcode: 2008Natur.455..547F. 
  13. ↑ "CDK8 is a stimulus-specific positive coregulator of p53 target genes". Molecular Cell 27 (1): 121–33. Jul 2007. doi:10.1016/j.molcel.2007.05.026. PMID 17612495. 
  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. ↑ "Mediator kinase inhibition further activates super-enhancer-associated genes in AML". Nature 526 (7572): 273–6. Oct 2015. doi:10.1038/nature14904. PMID 26416749. Bibcode: 2015Natur.526..273P. 
  16. ↑ 16.0 16.1 16.2 16.3 16.4 16.5 16.6 16.7 16.8 "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. doi:10.1073/pnas.261715899. PMID 11867769. Bibcode: 2002PNAS...99.2642K. 
  17. ↑ 17.0 17.1 17.2 17.3 "Characterization of mediator complexes from HeLa cell nuclear extract". Molecular and Cellular Biology 21 (14): 4604–13. Jul 2001. doi:10.1128/MCB.21.14.4604-4613.2001. PMID 11416138. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 "A human RNA polymerase II complex containing factors that modify chromatin structure". Molecular and Cellular Biology 18 (9): 5355–63. Sep 1998. doi:10.1128/MCB.18.9.5355. PMID 9710619. 
  19. ↑ "Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex". Cell 89 (3): 357–64. May 1997. doi:10.1016/s0092-8674(00)80216-0. PMID 9150135. 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 "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. doi:10.1016/s1097-2765(00)80463-3. PMID 10198638. 
  21. ↑ "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. doi:10.1128/MCB.17.10.6029. PMID 9315662. 
  22. ↑ "A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology". Molecular Cell 14 (5): 685–91. Jun 2004. doi:10.1016/j.molcel.2004.05.006. PMID 15175163. 
  23. ↑ "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. doi:10.1073/pnas.0308676100. PMID 14983011. Bibcode: 2004PNAS..101.2339Y. 

Further reading

External links



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