cyclin dependent kinases


Summary: Protein kinases that control cell cycle progression in all eukaryotes and require physical association with CYCLINS to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events.

Top Publications

  1. Akhtar M, Heidemann M, Tietjen J, Zhang D, Chapman R, Eick D, et al. TFIIH kinase places bivalent marks on the carboxy-terminal domain of RNA polymerase II. Mol Cell. 2009;34:387-93 pubmed publisher
    ..These bivalent CTD marks, in concert with cues within nascent transcripts, specify the cotranscriptional engagement of the relevant RNA processing machinery. ..
  2. Hong S, Hong S, Yoo J, Lee Y, Kim S, Lis J, et al. Phosphorylation of the RNA polymerase II C-terminal domain by TFIIH kinase is not essential for transcription of Saccharomyces cerevisiae genome. Proc Natl Acad Sci U S A. 2009;106:14276-80 pubmed publisher
    ..Therefore, contrary to the current belief, our study points strongly toward a minor role of TFIIH kinase in Pol II transcription, and a more significant role in mRNA capping in budding yeast. ..
  3. Butt A, Caldon C, McNeil C, Swarbrick A, Musgrove E, Sutherland R. Cell cycle machinery: links with genesis and treatment of breast cancer. Adv Exp Med Biol. 2008;630:189-205 pubmed
    ..Furthermore, a more detailed understanding of these pathways may identify new targets for therapeutic intervention particularly in endocrine-unresponsive and endocrine-resistant disease. ..
  4. McInnes C. Progress in the evaluation of CDK inhibitors as anti-tumor agents. Drug Discov Today. 2008;13:875-81 pubmed publisher
    ..has enabled the development of pharmacological agents inhibiting key regulatory proteins, with the cyclin dependent kinases (CDKs) representing a major area of interest...
  5. Tyson J, Novak B. Temporal organization of the cell cycle. Curr Biol. 2008;18:R759-R768 pubmed publisher
    ..The model accounts for the fundamental physiological properties of mitotic cell divisions, evokes a new view of the meiotic program, and suggests how the control system may have evolved in the first place. ..
  6. Hochegger H, Takeda S, Hunt T. Cyclin-dependent kinases and cell-cycle transitions: does one fit all?. Nat Rev Mol Cell Biol. 2008;9:910-6 pubmed publisher
    ..Recent work with gene-targeted mice has led to a revision of this model. We discuss cell-cycle control in light of overlapping and essential functions of the different CDKs and cyclins. ..
  7. Helenius K, Yang Y, Alasaari J, Makela T. Mat1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipocyte differentiation. Mol Cell Biol. 2009;29:315-23 pubmed publisher
    ..The observation that components of TFIIH are absent from transcriptionally active adipose tissue prompts a reevaluation of the ubiquitous nature of basal transcription factors in mammalian tissues. ..
  8. Baranello L, Bertozzi D, Fogli M, Pommier Y, Capranico G. DNA topoisomerase I inhibition by camptothecin induces escape of RNA polymerase II from promoter-proximal pause site, antisense transcription and histone acetylation at the human HIF-1alpha gene locus. Nucleic Acids Res. 2010;38:159-71 pubmed publisher
    ..A changed balance of antisense transcripts and mRNAs may then lead to altered regulation of HIF-1alpha activity in human cancer cells. ..
  9. Huertas P, Jackson S. Human CtIP mediates cell cycle control of DNA end resection and double strand break repair. J Biol Chem. 2009;284:9558-65 pubmed publisher
    ..These results suggest that CDK-mediated control of resection in human cells operates by mechanisms similar to those recently established in yeast. ..

More Information


  1. Knuesel M, Meyer K, Bernecky C, Taatjes D. The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function. Genes Dev. 2009;23:439-51 pubmed publisher
    ..As Mediator is generally required for expression of protein-coding genes, this may reflect a common mechanism by which activated transcription is shut down in human cells. ..
  2. Glover Cutter K, Larochelle S, Erickson B, Zhang C, Shokat K, Fisher R, et al. TFIIH-associated Cdk7 kinase functions in phosphorylation of C-terminal domain Ser7 residues, promoter-proximal pausing, and termination by RNA polymerase II. Mol Cell Biol. 2009;29:5455-64 pubmed publisher
    ..Consistent with a new role for TFIIH at 3' ends, it was detected within genes and 3'-flanking regions, and Cdk7 inhibition delayed pausing and transcription termination. ..
  3. Rao H, Thirumangalakudi L, Grammas P. Cyclin C and cyclin dependent kinases 1, 2 and 3 in thrombin-induced neuronal cell cycle progression and apoptosis. Neurosci Lett. 2009;450:347-50 pubmed publisher
    ..5h and the expression of cyclin C, cyclin dependent kinases (cdk1, cdk2, cdk3, cdk8) and the cell cycle inhibitor p27 assessed...
  4. Satyanarayana A, Kaldis P. Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms. Oncogene. 2009;28:2925-39 pubmed publisher
    ..Nevertheless, cell-cycle-independent functions of Cdks and cyclins such as in DNA damage repair are still under investigation. Here we review the compensatory mechanisms among major cyclins and Cdks in mammalian cell-cycle regulation. ..
  5. van Zon W, Ogink J, ter Riet B, Medema R, te Riele H, Wolthuis R. The APC/C recruits cyclin B1-Cdk1-Cks in prometaphase before D box recognition to control mitotic exit. J Cell Biol. 2010;190:587-602 pubmed publisher
    ..This suggests that the spindle checkpoint blocks D box recognition of APC/C-bound cyclin B1, whereas distinctive complexes between the N terminus of cyclin A and Cdc20 evade checkpoint control. ..
  6. Chen L, Nievera C, Lee A, Wu X. Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair. J Biol Chem. 2008;283:7713-20 pubmed publisher
  7. Basso A, Doll R. Inhibition of cyclin-dependent kinases - a review of the recent patent literature. Recent Pat Anticancer Drug Discov. 2006;1:357-67 pubmed
    The cyclin dependent kinases, Cdks, are potential targets for new anticancer therapy...
  8. Sharma P, Sharma R, Tyagi R. Inhibitors of cyclin dependent kinases: useful targets for cancer treatment. Curr Cancer Drug Targets. 2008;8:53-75 pubmed
    ..Over the past two decades, it has become increasingly clear that in many human cancers, hyperactivity of Cyclin Dependent Kinases (CDKs) is one of the mechanisms underlying the physiological hyper-proliferation...
  9. Warenius H, Seabra L, Kyritsi L, White R, Dormer R, Anandappa S, et al. Theranostic proteomic profiling of cyclins, cyclin dependent kinases and Ras in human cancer cell lines is dependent on p53 mutational status. Int J Oncol. 2008;32:895-907 pubmed
    ..We suggest that the theranostic relationships we have detected in vitro may have potential relevance in vivo and should prompt clinical theranostic studies which take account of p53 mutational status. ..
  10. Sordet O, Larochelle S, Nicolas E, Stevens E, Zhang C, Shokat K, et al. Hyperphosphorylation of RNA polymerase II in response to topoisomerase I cleavage complexes and its association with transcription- and BRCA1-dependent degradation of topoisomerase I. J Mol Biol. 2008;381:540-9 pubmed publisher
    ..Finally, we show that transcription-induced degradation of Top1 is Brca1 dependent, suggesting a role for Brca1 in the repair or removal of transcription-blocking Top1-DNA cleavage complexes. ..
  11. Viladevall L, St Amour C, Rosebrock A, Schneider S, Zhang C, Allen J, et al. TFIIH and P-TEFb coordinate transcription with capping enzyme recruitment at specific genes in fission yeast. Mol Cell. 2009;33:738-51 pubmed publisher
    ..In vitro, phosphorylation of the CTD by Mcs6 stimulates subsequent phosphorylation by Cdk9. We propose that TFIIH primes the CTD and promotes recruitment of P-TEFb/Pcm1, serving to couple elongation and capping of select pre-mRNAs. ..
  12. Brasier A. Expanding role of cyclin dependent kinases in cytokine inducible gene expression. Cell Cycle. 2008;7:2661-6 pubmed
    ..The potential of inhibiting P-TEFb as an anti-inflammatory therapy in innate immunity and systemic inflammation will be discussed. ..
  13. Coin F, Oksenych V, Mocquet V, Groh S, Blattner C, Egly J. Nucleotide excision repair driven by the dissociation of CAK from TFIIH. Mol Cell. 2008;31:9-20 pubmed publisher
    ..Our findings demonstrate that the composition of TFIIH is dynamic to adapt its engagement in distinct cellular processes. ..
  14. Martinsson Ahlzén H, Liberal V, Grünenfelder B, Chaves S, Spruck C, Reed S. Cyclin-dependent kinase-associated proteins Cks1 and Cks2 are essential during early embryogenesis and for cell cycle progression in somatic cells. Mol Cell Biol. 2008;28:5698-709 pubmed publisher
  15. Muramatsu S, Hirai K, Tak Y, Kamimura Y, Araki H. CDK-dependent complex formation between replication proteins Dpb11, Sld2, Pol (epsilon}, and GINS in budding yeast. Genes Dev. 2010;24:602-12 pubmed publisher
    ..We propose that CDK regulates the initiation of DNA replication in budding yeast through formation of the pre-LC. ..
  16. Andersen S, Buechel S, Zhao Z, Ljung K, Novak O, Busch W, et al. Requirement of B2-type cyclin-dependent kinases for meristem integrity in Arabidopsis thaliana. Plant Cell. 2008;20:88-100 pubmed publisher
    ..In addition, strong alterations in hormone signaling both at the level of active hormones and with respect to transcriptional and physiological outputs were observed in plants with disturbed CDKB2 activity. ..
  17. Wolthuis R, Clay Farrace L, van Zon W, Yekezare M, Koop L, Ogink J, et al. Cdc20 and Cks direct the spindle checkpoint-independent destruction of cyclin A. Mol Cell. 2008;30:290-302 pubmed publisher
    ..Thus, we identify a crucial role for the Cks proteins in mitosis and one mechanism by which the APC/C can target substrates independently of the spindle checkpoint. ..
  18. de Bruin R, Kalashnikova T, Wittenberg C. Stb1 collaborates with other regulators to modulate the G1-specific transcriptional circuit. Mol Cell Biol. 2008;28:6919-28 pubmed publisher
    ..The repression during G(1) also depends upon Sin3. We speculate that the interaction between Stb1 and Sin3 regulates the Sin3/HDAC complex at G(1)-specific promoters. ..
  19. Knuesel M, Meyer K, Donner A, Espinosa J, Taatjes D. The human CDK8 subcomplex is a histone kinase that requires Med12 for activity and can function independently of mediator. Mol Cell Biol. 2009;29:650-61 pubmed publisher
    ..In support of this, electron microscopy analysis suggests TRiC sequesters the CDK8 subcomplex and kinase assays reveal the endogenous CDK8 subcomplex--unlike the recombinant submodule--is unable to phosphorylate the Pol II CTD. ..
  20. Wagner M, Smolka M, de Bruin R, Zhou H, Wittenberg C, Dowdy S. Whi5 regulation by site specific CDK-phosphorylation in Saccharomyces cerevisiae. PLoS ONE. 2009;4:e4300 pubmed publisher
    ..Although these four Whi5 CDK sites do not wholly determine Whi5 nuclear export, they do impact regulation of cell size. Taken together, these observations begin to dissect the regulatory role of specific phosphorylation sites on Whi5. ..
  21. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153-66 pubmed publisher
    ..Emerging evidence suggests that tumour cells may also require specific interphase CDKs for proliferation. Thus, selective CDK inhibition may provide therapeutic benefit against certain human neoplasias. ..
  22. Gayther S, Song H, Ramus S, Kjaer S, Whittemore A, Quaye L, et al. Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer. Cancer Res. 2007;67:3027-35 pubmed
    ..This study highlights the need for multicenter collaborations for genetic association studies. ..
  23. Hu D, Valentine M, Kidd V, Lahti J. CDK11(p58) is required for the maintenance of sister chromatid cohesion. J Cell Sci. 2007;120:2424-34 pubmed
    ..These findings are consistent with the mitotic arrest we observed in CDK11-deficient mouse embryos and establish that CDK11(p58) is required for the maintenance of chromosome cohesion and the completion of mitosis. ..
  24. Schmid W, John R, Mühlgassner G, Heffeter P, Jakupec M, Galanski M, et al. Metal-based paullones as putative CDK inhibitors for antitumor chemotherapy. J Med Chem. 2007;50:6343-55 pubmed
    ..3)H-Thymidine incorporation assays revealed the compounds to lower the rate of DNA synthesis, and flow cytometric analyses showed cell cycle arrest mainly in G 0/ G 1 phase...
  25. Sinha I, Wang Y, Philp R, Li C, Yap W, Wang Y. Cyclin-dependent kinases control septin phosphorylation in Candida albicans hyphal development. Dev Cell. 2007;13:421-32 pubmed
    ..cerevisiae. Our study uncovers a direct link between the cell-cycle engine and the septin cytoskeleton that may be part of a conserved mechanism underlying polarized morphogenesis. ..
  26. Matsuno M, Kose H, Okabe M, Hiromi Y. TFIIH controls developmentally-regulated cell cycle progression as a holocomplex. Genes Cells. 2007;12:1289-300 pubmed
    ..We propose that during development the function of TFIIH as a cell cycle regulator is carried out by holo-TFIIH. ..
  27. Guo J, Song J, Wang F, Zhang X. Genome-wide identification and expression analysis of rice cell cycle genes. Plant Mol Biol. 2007;64:349-60 pubmed
    ..Our results provide basic information to understand the mechanism of cell cycle regulation and the functions of the rice cell cycle genes. ..
  28. Ito S, Kuraoka I, Chymkowitch P, Compe E, Takedachi A, Ishigami C, et al. XPG stabilizes TFIIH, allowing transactivation of nuclear receptors: implications for Cockayne syndrome in XP-G/CS patients. Mol Cell. 2007;26:231-43 pubmed
    ..These results provide an insight into the role of XPG in the stabilization of TFIIH and the regulation of gene expression and provide an explanation of some of the clinical features of XP-G/CS...
  29. Peres A, Churchman M, Hariharan S, Himanen K, Verkest A, Vandepoele K, et al. Novel plant-specific cyclin-dependent kinase inhibitors induced by biotic and abiotic stresses. J Biol Chem. 2007;282:25588-96 pubmed
    ..Orysa;EL2 mRNA levels were induced by cold, drought, and propionic acid. Our data suggest that Orysa;EL2 encodes a new type of plant CDK inhibitor that links cell cycle progression with biotic and abiotic stress responses. ..
  30. Santamaria D, Barrière C, Cerqueira A, Hunt S, Tardy C, Newton K, et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature. 2007;448:811-5 pubmed
    ..These results indicate that Cdk1 is the only essential cell cycle Cdk. Moreover, they show that in the absence of interphase Cdks, Cdk1 can execute all the events that are required to drive cell division. ..
  31. Sopko R, Huang D, Smith J, Figeys D, Andrews B. Activation of the Cdc42p GTPase by cyclin-dependent protein kinases in budding yeast. EMBO J. 2007;26:4487-500 pubmed
    ..Inhibition of GAPs by CDK phosphorylation may be a general mechanism to promote proper G1-phase progression. ..
  32. Chu Y, Simic R, Warner M, Arndt K, Prelich G. Regulation of histone modification and cryptic transcription by the Bur1 and Paf1 complexes. EMBO J. 2007;26:4646-56 pubmed
  33. Cheok C, Dey A, Lane D. Cyclin-dependent kinase inhibitors sensitize tumor cells to nutlin-induced apoptosis: a potent drug combination. Mol Cancer Res. 2007;5:1133-45 pubmed
  34. LARREA M, Wander S, Slingerland J. p27 as Jekyll and Hyde: regulation of cell cycle and cell motility. Cell Cycle. 2009;8:3455-61 pubmed
    ..Further characterization of post-translational modifications governing p27 localization and its action on RhoA and the actin cytoskeleton may provide critical insights into human cancer metastasis. ..
  35. Cook J. Replication licensing and the DNA damage checkpoint. Front Biosci (Landmark Ed). 2009;14:5013-30 pubmed
    ..These findings suggest that checkpoints and replication are more intimately associated than previously appreciated, even in the absence of exogenous DNA damage. This review summarizes some of these developments. ..
  36. Horiuchi T, Nagata M, Kitagawa M, Akahane K, Uoto K. Discovery of novel thieno[2,3-d]pyrimidin-4-yl hydrazone-based inhibitors of cyclin D1-CDK4: synthesis, biological evaluation and structure-activity relationships. Part 2. Bioorg Med Chem. 2009;17:7850-60 pubmed publisher
    ..In this paper, the potency, selectivity profile and structure-activity relationships of our synthetic compounds are discussed. ..
  37. Wang Z, Lee H, Chai Y, Hu H, Wang L, Zhang Y, et al. Persistent p21Cip1 induction mediates G(1) cell cycle arrest by methylseleninic acid in DU145 prostate cancer cells. Curr Cancer Drug Targets. 2010;10:307-18 pubmed
  38. He R, Chen Y, Chen Y, Ougolkov A, Zhang J, Savoy D, et al. Synthesis and biological evaluation of triazol-4-ylphenyl-bearing histone deacetylase inhibitors as anticancer agents. J Med Chem. 2010;53:1347-56 pubmed publisher
    ..Taken together, these data further support the value of the triazol-4-ylphenyl bearing hydroxamates in identifying potential pancreatic cancer therapies. ..
  39. Bartkowiak B, Liu P, Phatnani H, Fuda N, Cooper J, Price D, et al. CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1. Genes Dev. 2010;24:2303-16 pubmed publisher
    ..Finally, we show that siRNA knockdown of hCDK12 in HeLa cells results in alterations in the CTD phosphorylation state. Our findings demonstrate that metazoan CDK12 and CDK13 are CTD kinases, and that CDK12 is orthologous to yeast Ctk1. ..
  40. Kobayashi Y, Kanesaki Y, Tanaka A, Kuroiwa H, Kuroiwa T, Tanaka K. Tetrapyrrole signal as a cell-cycle coordinator from organelle to nuclear DNA replication in plant cells. Proc Natl Acad Sci U S A. 2009;106:803-7 pubmed publisher
    ..We thus show that tetrapyrrole-mediated organelle-nucleus replicational coupling is an evolutionary conserved process among plant cells. ..
  41. Loyer P, Trembley J, Grenet J, Busson A, Corlu A, Zhao W, et al. Characterization of cyclin L1 and L2 interactions with CDK11 and splicing factors: influence of cyclin L isoforms on splice site selection. J Biol Chem. 2008;283:7721-32 pubmed publisher
    ..Together, these data establish that CDK11(p110) interacts physically and functionally with cyclin Lalpha and -beta isoforms and SR proteins to regulate splicing. ..
  42. Rosner M, Dolznig H, Fuchs C, Siegel N, Valli A, Hengstschlager M. CDKs as therapeutic targets for the human genetic disease tuberous sclerosis?. Eur J Clin Invest. 2009;39:1033-5 pubmed publisher
    ..Taken together, these findings strengthen the argument that besides mTOR-inhibitors, such as rapamycin analogues, p27 and CDKs could also be considered targets for hamartoma therapeutics in tuberous sclerosis. ..
  43. Rocha A, Paternot S, Coulonval K, Dumont J, Soares P, Roger P. Cyclic AMP inhibits the proliferation of thyroid carcinoma cell lines through regulation of CDK4 phosphorylation. Mol Biol Cell. 2008;19:4814-25 pubmed publisher
  44. Mizutani M, Naganuma T, Tsutsumi K, Saitoh Y. The syncytium-specific expression of the Orysa;KRP3 CDK inhibitor: implication of its involvement in the cell cycle control in the rice (Oryza sativa L.) syncytial endosperm. J Exp Bot. 2010;61:791-8 pubmed publisher
    ..These data suggest that Orysa;KRP3 is involved in cell cycle control of syncytial endosperm...
  45. Yoshida K, Sugimoto N, Iwahori S, Yugawa T, Narisawa Saito M, Kiyono T, et al. CDC6 interaction with ATR regulates activation of a replication checkpoint in higher eukaryotic cells. J Cell Sci. 2010;123:225-35 pubmed publisher
    ..Thus, CDC6 might regulate replication-checkpoint activation through the interaction with ATR in higher eukaryotic cells...
  46. C zkov M, Pichov A, V tov M, Hlavov M, Hendrychov J, Umysov D, et al. CDKA and CDKB kinases from Chlamydomonas reinhardtii are able to complement cdc28 temperature-sensitive mutants of Saccharomyces cerevisiae. Protoplasma. 2008;232:183-91 pubmed publisher
    ..reinhardtii. The complementation of the mitotic phenotype of the S. cerevisiae cdc28-1N mutant suggests a mitotic role for both of the kinases...
  47. Kerr N, Pintzas A, Holmes F, Hobson S, Pope R, Wallace M, et al. The expression of ELK transcription factors in adult DRG: Novel isoforms, antisense transcripts and upregulation by nerve damage. Mol Cell Neurosci. 2010;44:165-77 pubmed publisher
    ..3-fold in DRG (P<0.005), whereas the natural antisense Pctaire2 isoforms show only a small increase (21%, P<0.01) and Elk1 and Elk4 mRNAs are unchanged. ..
  48. Huang Y, Tsay W, Chen C, Lin C, Huang H. Increased expression of the rice C-type cyclin-dependent protein kinase gene, Orysa;CDKC;1, in response to salt stress. Plant Physiol Biochem. 2008;46:71-81 pubmed
    ..In addition, the MBP kinase activity associated with Orysa;CDKC;1 immunocomplexes was induced under salt stress. We propose that Orysa;CDKC;1 may be involved in developmental programs, as well as in the salt- and ABA-signaling pathway. ..
  49. Kim S, Gadiparthi K, Kron S, Kitazono A. A phosphorylation-independent role for the yeast cyclin-dependent kinase activating kinase Cak1. Gene. 2009;447:97-105 pubmed publisher
    ..While Cak1 is constitutively active and expressed, dividing cells tightly regulate Cak1 protein levels to ensure presence of adequate levels of Cdc28 CDK activity. ..
  50. Shi J, Hershey J, Nelson M. Phosphorylation of the eukaryotic initiation factor 3f by cyclin-dependent kinase 11 during apoptosis. FEBS Lett. 2009;583:971-7 pubmed publisher
    ..Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis. Our data suggested that eIF3f may inhibit translation by increasing the binding to the eIF3 complex during apoptosis. ..
  51. Cuomo M, Knebel A, Morrice N, Paterson H, Cohen P, Mittnacht S. p53-Driven apoptosis limits centrosome amplification and genomic instability downstream of NPM1 phosphorylation. Nat Cell Biol. 2008;10:723-30 pubmed publisher
    ..Our findings provide evidence that abnormal chromosome segregation in KSHV-infected cells is a direct consequence of NPM1 phosphorylation and predict that genomic instability is an inevitable consequence of latent KSHV infection. ..
  52. Schmitz M, Held M, Janssens V, Hutchins J, Hudecz O, Ivanova E, et al. Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-beta1 as key mitotic exit regulators in human cells. Nat Cell Biol. 2010;12:886-93 pubmed publisher
    ..This demonstrates that PP2A-B55alpha and importin-beta1 cooperate in the regulation of postmitotic assembly mechanisms in human cells. ..
  53. Obligado S, Ibraghimov Beskrovnaya O, Zuk A, Meijer L, Nelson P. CDK/GSK-3 inhibitors as therapeutic agents for parenchymal renal diseases. Kidney Int. 2008;73:684-90 pubmed
    ..Novel biomarkers of therapy are aiding the process of drug development. This review will highlight these advancements in renal therapeutics. ..