Gene Symbol: Cdk4
Description: Cyclin-dependent kinase 4
Alias: CDK4, CDK4/6, CG5072, Cdk4/6, DmCdk4, Dmel\CG5072, Pk53C, Pk?7, cdk, cdk4, cdk4/6, dCdk4, l(2)05428, l(2)0671, l(2)k06503, l(2)s4639, l(2)sh0671, Cyclin-dependent kinase 4, CG5072-PA, CG5072-PB, CG5072-PC, CG5072-PD, CG5072-PE, Cdk4-PA, Cdk4-PB, Cdk4-PC, Cdk4-PD, Cdk4-PE, Cyclin-dependent kinase 4/6, cyclin-dependent kinase 4, protein kinase-like 53C
Species: fruit fly

Top Publications

  1. Meyer C, Jacobs H, Datar S, Du W, Edgar B, Lehner C. Drosophila Cdk4 is required for normal growth and is dispensable for cell cycle progression. EMBO J. 2000;19:4533-42 pubmed
    Complexes of D-type cyclins and cdk4 or 6 are thought to govern progression through the G(1) phase of the cell cycle. In Drosophila, single genes for Cyclin D and Cdk4 have been identified, simplifying genetic analysis...
  2. Frei C, Galloni M, Hafen E, Edgar B. The Drosophila mitochondrial ribosomal protein mRpL12 is required for Cyclin D/Cdk4-driven growth. EMBO J. 2005;24:623-34 pubmed
    The Drosophila melanogaster cyclin-dependent protein kinase complex CycD/Cdk4 stimulates both cell cycle progression and cell growth (accumulation of mass)...
  3. Scott R, Schuldiner O, Neufeld T. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev Cell. 2004;7:167-78 pubmed
    ..Thus, in cells lacking TOR, autophagy plays a protective role that is dominant over its potential role as a growth suppressor. ..
  4. Datar S, Galloni M, de la Cruz A, Marti M, Edgar B, Frei C. Mammalian cyclin D1/Cdk4 complexes induce cell growth in Drosophila. Cell Cycle. 2006;5:647-52 pubmed
    The Drosophila melanogaster cyclin dependent protein kinase complex CycD/Cdk4 has been shown to regulate cellular growth (accumulation of mass) as well as proliferation (cell cycle progression)...
  5. Datar S, Jacobs H, de la Cruz A, Lehner C, Edgar B. The Drosophila cyclin D-Cdk4 complex promotes cellular growth. EMBO J. 2000;19:4543-54 pubmed
    Mammalian cyclin D-Cdk4 complexes have been characterized as growth factor-responsive cell cycle regulators...
  6. Frolov M, Stevaux O, Moon N, Dimova D, Kwon E, Morris E, et al. G1 cyclin-dependent kinases are insufficient to reverse dE2F2-mediated repression. Genes Dev. 2003;17:723-8 pubmed
    ..1 (RBF1) inhibition of dE2F1, and is resistant to both CycE/cdk2 and Cyclin D/cyclin-dependent kinase 4 (CycD/cdk4)...
  7. Buttitta L, Katzaroff A, Perez C, de la Cruz A, Edgar B. A double-assurance mechanism controls cell cycle exit upon terminal differentiation in Drosophila. Dev Cell. 2007;12:631-43 pubmed terminally differentiating cells by the simultaneous activation of E2F1 and either Cyclin E/Cdk2 or Cyclin D/Cdk4. Enforcing both E2F and Cyclin/Cdk activities is required to bypass exit because feedback between E2F and Cyclin E/..
  8. Hamaratoglu F, Gajewski K, Sansores Garcia L, Morrison C, Tao C, Halder G. The Hippo tumor-suppressor pathway regulates apical-domain size in parallel to tissue growth. J Cell Sci. 2009;122:2351-9 pubmed publisher
    ..Therefore, Hippo signaling regulates cell polarity complexes in addition to and independently of its growth control function in imaginal disc cells. ..
  9. Emmerich J, Meyer C, de la Cruz A, Edgar B, Lehner C. Cyclin D does not provide essential Cdk4-independent functions in Drosophila. Genetics. 2004;168:867-75 pubmed
    ..As previously observed with null mutations in the single Drosophila Cdk4 gene, these mutations do not primarily affect progression through the G1 phase...

More Information


  1. Genevet A, Polesello C, Blight K, Robertson F, Collinson L, Pichaud F, et al. The Hippo pathway regulates apical-domain size independently of its growth-control function. J Cell Sci. 2009;122:2360-70 pubmed publisher
    ..Therefore, Hippo signalling controls growth and apical domain size by distinct mechanisms. ..
  2. Icreverzi A, de la Cruz A, Van Voorhies W, Edgar B. Drosophila cyclin D/Cdk4 regulates mitochondrial biogenesis and aging and sensitizes animals to hypoxic stress. Cell Cycle. 2012;11:554-68 pubmed publisher
    ..However, little is known about how CycD promotes cell growth. We show here that CycD/Cdk4 hyperactivity leads to increased mitochondrial biogenesis (mitobiogenesis), mitochondrial mass, NRF-1 activity (..
  3. Liu J, Kipreos E. Evolution of cyclin-dependent kinases (CDKs) and CDK-activating kinases (CAKs): differential conservation of CAKs in yeast and metazoa. Mol Biol Evol. 2000;17:1061-74 pubmed
    Cyclin-dependent kinases (CDKs) function as central regulators of both the cell cycle and transcription. CDK activation depends on phosphorylation by a CDK-activating kinase (CAK)...
  4. Nolo R, Morrison C, Tao C, Zhang X, Halder G. The bantam microRNA is a target of the hippo tumor-suppressor pathway. Curr Biol. 2006;16:1895-904 pubmed
    ..Our data indicate that bantam is an essential target of the Hippo signaling pathway to regulate cell proliferation, cell death, and thus tissue size. ..
  5. Baltzer C, Tiefenböck S, Marti M, Frei C. Nutrition controls mitochondrial biogenesis in the Drosophila adipose tissue through Delg and cyclin D/Cdk4. PLoS ONE. 2009;4:e6935 pubmed publisher
    ..Our data demonstrate that Delg is critical to adjust mitochondrial abundance in respect to Cyclin D/Cdk4, a growth-promoting complex and glutamine metabolism according to nutrient availability...
  6. Baumgardt M, Karlsson D, Salmani B, Bivik C, MacDonald R, Gunnar E, et al. Global programmed switch in neural daughter cell proliferation mode triggered by a temporal gene cascade. Dev Cell. 2014;30:192-208 pubmed publisher
    ..This reveals a logical principle underlying progenitor and daughter cell proliferation control in the Drosophila CNS. ..
  7. Li L, Anderson S, Secombe J, Eisenman R. The Drosophila ubiquitin-specific protease Puffyeye regulates dMyc-mediated growth. Development. 2013;140:4776-87 pubmed publisher
    ..In addition to its effects on dMyc, Puf regulates both Ago and its cell cycle substrate Cyclin E. Therefore, Puf influences cell growth by controlling the stability of key regulatory proteins. ..
  8. Hétié P, de Cuevas M, Matunis E. Conversion of quiescent niche cells to somatic stem cells causes ectopic niche formation in the Drosophila testis. Cell Rep. 2014;7:715-21 pubmed publisher
    ..Ectopic Cyclin D-Cdk4 expression in hub cells is also sufficient to trigger their conversion into CySCs...
  9. Rafel N, Milan M. Notch signalling coordinates tissue growth and wing fate specification in Drosophila. Development. 2008;135:3995-4001 pubmed publisher
    ..These results highlight a crucial role of Notch in linking proliferation and fate specification in the developing wing primordium. ..
  10. Edgar B, Orr Weaver T. Endoreplication cell cycles: more for less. Cell. 2001;105:297-306 pubmed
  11. Shingleton A. Body-size regulation: combining genetics and physiology. Curr Biol. 2005;15:R825-7 pubmed
    ..New research has revealed that the activity of the insulin-signaling pathway in the prothoracic gland of Drosophila modulates ecdysone release and thereby influences both the duration and rate of larval growth. ..
  12. de la Cova C, Abril M, Bellosta P, Gallant P, Johnston L. Drosophila myc regulates organ size by inducing cell competition. Cell. 2004;117:107-16 pubmed
    ..Modulating dmyc levels to create cell competition and hid-dependent cell death may be a mechanism used during normal development to control organ size. ..
  13. Baker N. Developmental regulation of nucleolus size during Drosophila eye differentiation. PLoS ONE. 2013;8:e58266 pubmed publisher
  14. Smith Bolton R, Worley M, Kanda H, Hariharan I. Regenerative growth in Drosophila imaginal discs is regulated by Wingless and Myc. Dev Cell. 2009;16:797-809 pubmed publisher
    ..This system is conducive to forward genetic screens, enabling an unbiased search for genes that regulate both the extent of and the capacity for regeneration. ..
  15. Silver D, Montell D. A new trick for Cyclin-Cdk: activation of STAT. Dev Cell. 2003;4:148-9 pubmed
    New work in Drosophila demonstrates that cdk4 loss causes phenotypes similar to the loss of JAK/STAT pathway components. Cdk4 overexpression can bypass requirements for JAK but not STAT...
  16. Frei C, Edgar B. Drosophila cyclin D/Cdk4 requires Hif-1 prolyl hydroxylase to drive cell growth. Dev Cell. 2004;6:241-51 pubmed
    The Drosophila cyclin-dependent protein kinase complex Cyclin D/Cdk4 induces cell growth (accumulation of mass) as well as proliferation (cell cycle progression)...
  17. Adlesic M, Frei C, Frew I. Cdk4 functions in multiple cell types to control Drosophila intestinal stem cell proliferation and differentiation. Biol Open. 2016;5:237-51 pubmed publisher
    ..We show that genetic modulation of CyclinD/Cdk4 activity or mTOR-dependent signalling cell-autonomously regulates enterocyte growth, which influences ISC ..
  18. Zhang L, Wei Y, Pushel I, Heinze K, Elenbaas J, Henry R, et al. Integrated stability and activity control of the Drosophila Rbf1 retinoblastoma protein. J Biol Chem. 2014;289:24863-73 pubmed publisher
    ..understand how activity and turnover are controlled in this model RB protein, we assessed the impact of Cyclin-Cdk kinase regulation on Rbf1...
  19. Coffman C, Wayne M, Nuzhdin S, Higgins L, McIntyre L. Identification of co-regulated transcripts affecting male body size in Drosophila. Genome Biol. 2005;6:R53 pubmed
    ..Applied to body size in Drosophila simulans, an evolutionarily important complex trait, a factor was directly associated with body size. ..
  20. Kim W, Jang Y, Yang J, Chung J. Spatial Activation of TORC1 Is Regulated by Hedgehog and E2F1 Signaling in the Drosophila Eye. Dev Cell. 2017;42:363-375.e4 pubmed publisher
    ..We demonstrated that Hedgehog (Hh) signaling regulates TORC1 through E2F1 and the cyclin D/Cdk4 complex in the SMW, and this regulation is independent from insulin and amino acid signaling pathways...
  21. Duronio R. A breath of fresh air for cyclin D/Cdk4: triggering growth via Hph. Dev Cell. 2004;6:163-4 pubmed
    Activation of Cyclin D/Cdk4 stimulates progression through the G1-S phase of the cell cycle in many organisms. In Drosophila, Cyclin D/Cdk4 also induces cell growth independently of cell cycle progression...
  22. Moberg K, Hariharan I. Big things from a little RNA. Trends Cell Biol. 2003;13:455-7 pubmed
  23. Bateman J, McNeill H. Temporal control of differentiation by the insulin receptor/tor pathway in Drosophila. Cell. 2004;119:87-96 pubmed
    ..These data suggest that intricate developmental decisions are coordinated with nutritional status and tissue growth by the InR signaling pathway. ..
  24. Sauer K, Weigmann K, Sigrist S, Lehner C. Novel members of the cdc2-related kinase family in Drosophila: cdk4/6, cdk5, PFTAIRE, and PITSLRE kinase. Mol Biol Cell. 1996;7:1759-69 pubmed
    ..Sequence comparisons suggest that the four putative kinases represent the Drosophila homologues of vertebrate cdk4/6, cdk5, PCTAIRE, and PITSLRE kinases...
  25. Xin S, Weng L, Xu J, Du W. The role of RBF in developmentally regulated cell proliferation in the eye disc and in Cyclin D/Cdk4 induced cellular growth. Development. 2002;129:1345-56 pubmed
    ..Characterization of the role of RBF in Cyclin D/Cdk4-mediated cellular growth showed that RBF-280 blocks Cyclin D/Cdk4 induced cellular growth in the proliferating wing ..
  26. Gupta R, Tripathi R, Naidu B, Srinivas U, Shashidhara L. Cell cycle regulation by the pro-apoptotic gene Scotin. Cell Cycle. 2008;7:2401-8 pubmed
    ..Furthermore, a larger proportion of cells overexpressing Scotin showed sequestration of Cyclin B1 in the cytoplasm. These results suggest that one of the ways by which Scotin induces apoptosis is by causing cell cycle arrest. ..
  27. Berry D, Baehrecke E. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell. 2007;131:1137-48 pubmed
  28. Sasai N, Kato Y, Kimura G, Takeuchi T, Yamaguchi M. The Drosophila jumonji gene encodes a JmjC-containing nuclear protein that is required for metamorphosis. FEBS J. 2007;274:6139-51 pubmed
    ..These findings suggest that dJmj controls expression of developmentally important genes through modification of chromatin into a transcriptionally silenced state. ..
  29. Lu J, Ruhf M, Perrimon N, Leder P. A genome-wide RNA interference screen identifies putative chromatin regulators essential for E2F repression. Proc Natl Acad Sci U S A. 2007;104:9381-6 pubmed
    ..These findings suggest that potential chromatin regulation mediated by Domino and PcG-like factors plays an important role in controlling E2F activity and cell growth. ..
  30. Tseng A, Tapon N, Kanda H, Cigizoglu S, Edelmann L, Pellock B, et al. Capicua regulates cell proliferation downstream of the receptor tyrosine kinase/ras signaling pathway. Curr Biol. 2007;17:728-33 pubmed
    ..Thus, the DNA-binding protein Cic is a key downstream component in the pathway by which Ras regulates growth in imaginal discs. ..
  31. Kalderon D, Rubin G. Isolation and characterization of Drosophila cAMP-dependent protein kinase genes. Genes Dev. 1988;2:1539-56 pubmed
    ..The remaining putative gene products include amino acid sequence motifs characteristic of serine-threonine protein kinases but cannot, from the available data, be defined as homologous to specific protein kinases of other organisms. ..
  32. Tiefenböck S, Baltzer C, Egli N, Frei C. The Drosophila PGC-1 homologue Spargel coordinates mitochondrial activity to insulin signalling. EMBO J. 2010;29:171-83 pubmed publisher
    ..Taken together, our data place Spargel at a nodal point for the integration of mitochondrial activity to tissue and organismal metabolism and growth. ..
  33. Chen X, Oh S, Zheng Z, Chen H, Shin H, Hou S. Cyclin D-Cdk4 and cyclin E-Cdk2 regulate the Jak/STAT signal transduction pathway in Drosophila. Dev Cell. 2003;4:179-90 pubmed
    ..In this report, we identify the Drosophila cyclin-dependent kinase 4 (Cdk4), which exhibits embryonic mutant phenotypes identical to those in the Hopscotch/JAK kinase and stat92E/STAT ..
  34. Jaklevic B, Uyetake L, Lemstra W, Chang J, Leary W, Edwards A, et al. Contribution of growth and cell cycle checkpoints to radiation survival in Drosophila. Genetics. 2006;174:1963-72 pubmed
    ..or onset of pupariation) or inhibition of growth factor signaling and downstream targets (by mutations in cdk4, chico, or dmyc) reduced the radiation survival of larvae...
  35. Lorén C, Scully A, Grabbe C, Edeen P, Thomas J, McKeown M, et al. Identification and characterization of DAlk: a novel Drosophila melanogaster RTK which drives ERK activation in vivo. Genes Cells. 2001;6:531-44 pubmed
    ..Expression patterns of dALK, together with activated ERK, suggest that DAlk fulfils the criteria of the missing RTK pathway, leading to ERK activation in the developing visceral mesoderm. ..
  36. Mika S, Rost B. Protein-protein interactions more conserved within species than across species. PLoS Comput Biol. 2006;2:e79 pubmed
    ..More comprehensive images of protein-protein networks will require the combination of many high-throughput methods, including in silico inferences and predictions. ..
  37. Parisi F, Riccardo S, Zola S, Lora C, Grifoni D, Brown L, et al. dMyc expression in the fat body affects DILP2 release and increases the expression of the fat desaturase Desat1 resulting in organismal growth. Dev Biol. 2013;379:64-75 pubmed publisher
    ..Expression of dMyc, but not of CycD/cdk4 or Rheb, in the FB diminishes the ability to retain Drosophila Insulin-like peptide-2 (DILP2) in the brain during ..
  38. Djiane A, Shimizu H, Wilkin M, Mazleyrat S, Jennings M, Avis J, et al. Su(dx) E3 ubiquitin ligase-dependent and -independent functions of polychaetoid, the Drosophila ZO-1 homologue. J Cell Biol. 2011;192:189-200 pubmed publisher
    ..As both Su(dx) and Expanded regulate trafficking, we propose that a conserved role of ZO proteins is to coordinate receptor trafficking and signaling with junctional organization. ..
  39. Meyer C, Jacobs H, Lehner C. Cyclin D-cdk4 is not a master regulator of cell multiplication in Drosophila embryos. Curr Biol. 2002;12:661-6 pubmed
    ..of Cyclin E-Cdk2 required for the epidermal cell proliferation arrest occurs as a consequence of Cyclin D-Cdk4 inactivation...
  40. Nicholson S, Gilbert M, Nicolay B, Frolov M, Moberg K. The archipelago tumor suppressor gene limits rb/e2f-regulated apoptosis in developing Drosophila tissues. Curr Biol. 2009;19:1503-10 pubmed publisher
    ..Moreover, the susceptibility of ago mutant cells to succumb to this apoptotic program appears to depend on local variations in extracellular signaling that could thus determine tissue-specific fates of ago mutant cells. ..
  41. Morris E, Michaud W, Ji J, Moon N, Rocco J, Dyson N. Functional identification of Api5 as a suppressor of E2F-dependent apoptosis in vivo. PLoS Genet. 2006;2:e196 pubmed
    ..Therefore, inhibition of Api5 function might offer a possible mechanism for antitumor exploitation. ..
  42. Faradji F, Bloyer S, Dardalhon Cuménal D, Randsholt N, Peronnet F. Drosophila melanogaster Cyclin G coordinates cell growth and cell proliferation. Cell Cycle. 2011;10:805-18 pubmed
    ..Control of cell growth and cell cycle by Cyclin G might be achieved via interaction with a network of partners, notably the cyclin-dependent kinases CDK4 and CDK2.
  43. Flannery E, VanZomeren Dohm A, Beach P, Holland W, Duman Scheel M. Induction of cellular growth by the axon guidance regulators netrin A and semaphorin-1a. Dev Neurobiol. 2010;70:473-84 pubmed publisher
    ..indicated that NetA and Sema1a signaling induce expression of several growth regulators, including myc, cycD, cdk4, PCNA, and MapK in the wing disc...
  44. Khurana V, Lu Y, Steinhilb M, Oldham S, Shulman J, Feany M. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr Biol. 2006;16:230-41 pubmed
    ..TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model, identifying TOR and the cell cycle as potential therapeutic targets in tauopathies and AD. ..
  45. Martín Castellanos C, Edgar B. A characterization of the effects of Dpp signaling on cell growth and proliferation in the Drosophila wing. Development. 2002;129:1003-13 pubmed
    ..The growth response to altering Dpp signaling varied regionally and temporally in the wing disc, indicating that other patterned factors modify the response. ..
  46. Hipfner D, Weigmann K, Cohen S. The bantam gene regulates Drosophila growth. Genetics. 2002;161:1527-37 pubmed
    ..These effects are strikingly similar to those associated with alterations in the activity of the cyclinD-cdk4 complex...
  47. Debat V, Bloyer S, Faradji F, Gidaszewski N, Navarro N, Orozco Terwengel P, et al. Developmental stability: a major role for cyclin G in drosophila melanogaster. PLoS Genet. 2011;7:e1002314 pubmed publisher
    ..We discuss the possible role of CycG as a hub in a genetic network that controls developmental stability. ..
  48. Gilboa L, Lehmann R. Soma-germline interactions coordinate homeostasis and growth in the Drosophila gonad. Nature. 2006;443:97-100 pubmed
    ..We propose that similar feedback mechanisms might be generally used for coordinated growth, regeneration and homeostasis. ..
  49. Foley E, Sprenger F. Cyclins: growing pains for Drosophila. Curr Biol. 2000;10:R665-7 pubmed
    ..Tradition holds that cyclin D is required for the initiation of cell division; recent studies in Drosophila, however, suggest that cyclin D has a separate function in governing growth. ..
  50. Icreverzi A, de la Cruz A, Walker D, Edgar B. Changes in neuronal CycD/Cdk4 activity affect aging, neurodegeneration, and oxidative stress. Aging Cell. 2015;14:896-906 pubmed publisher
    ..The Drosophila Cyclin-dependent protein kinase complex cyclin D/cyclin-dependent kinase 4 (CycD/Cdk4) promotes cellular growth by stimulating mitochondrial biogenesis...
  51. McClure K, Schubiger G. Developmental analysis and squamous morphogenesis of the peripodial epithelium in Drosophila imaginal discs. Development. 2005;132:5033-42 pubmed
    ..Finally, by lineage tracing cells in the PE, we surprisingly find that peripodial cells are displaced into the disc proper during larval development and this movement leads to Ubx repression. ..
  52. Bergmann A, Lane M. HIDden targets of microRNAs for growth control. Trends Biochem Sci. 2003;28:461-3 pubmed
    ..Recent advances in Drosophila research have implicated a microRNA as an important regulator of animal size. These studies reveal an unexpected layer of size regulation in higher animals. ..
  53. Meyer C, Kramer I, Dittrich R, Marzodko S, Emmerich J, Lehner C. Drosophila p27Dacapo expression during embryogenesis is controlled by a complex regulatory region independent of cell cycle progression. Development. 2002;129:319-28 pubmed
    ..The dacapo regulatory region includes many independent cis-regulatory elements. The elements that control epidermal expression integrate developmental cues that time the arrest of cell proliferation...
  54. Tapon N, Moberg K, Hariharan I. The coupling of cell growth to the cell cycle. Curr Opin Cell Biol. 2001;13:731-7 pubmed
    ..This work has revealed interesting and unexpected relationships between mechanisms that regulate growth and the cell cycle machinery. ..
  55. Layalle S, Arquier N, Leopold P. The TOR pathway couples nutrition and developmental timing in Drosophila. Dev Cell. 2008;15:568-77 pubmed publisher
    ..In conclusion, the PG uses TOR signaling to couple nutritional input with ecdysone production and developmental timing. ..
  56. Zhong J, Zhang H, Stanyon C, Tromp G, Finley R. A strategy for constructing large protein interaction maps using the yeast two-hybrid system: regulated expression arrays and two-phase mating. Genome Res. 2003;13:2691-9 pubmed
    ..We also present a three-dimensional pooling scheme to further increase the efficiency of large-scale two-hybrid analyses. ..
  57. Duman Scheel M, Weng L, Xin S, Du W. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature. 2002;417:299-304 pubmed
    ..The discovery of a direct connection between Hh signalling and principal cell-cycle regulators provides insight into the mechanism by which deregulated Hh signalling promotes tumour formation. ..
  58. Tapon N, Ito N, Dickson B, Treisman J, Hariharan I. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell. 2001;105:345-55 pubmed
    ..In postmitotic mutant cells, levels of Cyclin E and Cyclin A are elevated. This correlates with a tendency for these cells to reenter the cell cycle inappropriately as is observed in the human lesions. ..
  59. Kolonin M, Finley R. Targeting cyclin-dependent kinases in Drosophila with peptide aptamers. Proc Natl Acad Sci U S A. 1998;95:14266-71 pubmed
    ..Expression of each Cdk aptamer during organogenesis caused adult eye defects typical of those caused by cell cycle inhibition...