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Cyclin-Dependent Kinases and Their Regulators as Potential Targets for Anticancer Therapeutics

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References

  1. 1. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer 2003;3:459–465.

    Article  PubMed  CAS  Google Scholar 

  2. 2. Hartwell LH, Culotti J, Reid B. Genetic control of the cell-division cycle in yeast. I. Detection of mutants. Proc Natl Acad Sci USA 1970;66:352–359.

    Article  PubMed  CAS  Google Scholar 

  3. 3. Hartwell LH, Culotti J, Pringle JR, Reid BJ. Genetic control of the cell division cycle in yeast. Science 1974;183:46–51.

    Article  PubMed  CAS  Google Scholar 

  4. 4. Hartwell LH, Weinert TA. Checkpoints: controls that ensure the order of cell cycle events. Science 1989;246:629–634.

    Article  PubMed  CAS  Google Scholar 

  5. 5. Nurse P, Thuriaux P. Regulatory genes controlling mitosis in the fission yeast Schizosaccharomyces pombe. Genetics 1980;96:627–637.

    PubMed  CAS  Google Scholar 

  6. 6. Simanis V, Nurse P. The cell cycle control gene cdc2+ of fission yeast encodes a protein kinase potentially regulated by phosphorylation. Cell 1986;45:261–268.

    Article  PubMed  CAS  Google Scholar 

  7. 7. Evans T, Rosenthal ET, Youngblom J, Distel D, Hunt T. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 1983;33:389–396.

    Article  PubMed  CAS  Google Scholar 

  8. 8. Gautier J, Norbury C, Lohka M, Nurse P, Maller J. Purified maturation-promoting factor contains the product of a Xenopus homolog of the fission yeast cell cycle control gene cdc2+. Cell 1988;54:433–439.

    Article  PubMed  CAS  Google Scholar 

  9. 9. Gautier J, Minshull J, Lohka M, Glotzer M, Hunt T, Maller JL. Cyclin is a component of maturation-promoting factor from Xenopus. Cell 1990;60:487–494.

    Article  PubMed  CAS  Google Scholar 

  10. 10. Draetta G, Brizuela L, Potashkin J, Beach D. Identification of p34 and p13, human homologs of the cell cycle regulators of fission yeast encoded by cdc2+ and suc1+. Cell 1987;50:319–325.

    Article  PubMed  CAS  Google Scholar 

  11. 11. Lee MG, Nurse P. Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2. Nature 1987;327:31–35.

    Article  PubMed  CAS  Google Scholar 

  12. 12. Hanks SK. Homology probing: identification of cDNA clones encoding members of the protein-serine kinase family. Proc Natl Acad Sci USA 1987;84:388–392.

    Article  PubMed  CAS  Google Scholar 

  13. 13. Elledge SJ, Spottswood MR. A new human p34 protein kinase, CDK2, identified by complementation of a cdc28 mutation in Saccharomyces cerevisiae, is a homolog of Xenopus Eg1. Embo J 1991;10:2653–2659.

    PubMed  CAS  Google Scholar 

  14. 14. Paris J, Le Guellec R, Couturier A, et al. Cloning by differential screening of a Xenopus cDNA coding for a protein highly homologous to cdc2. Proc Natl Acad Sci USA 1991;88:1039–1043.

    Article  PubMed  CAS  Google Scholar 

  15. 15. Tsai LH, Harlow E, Meyerson M. Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase. Nature 1991;353:174–177.

    Article  PubMed  CAS  Google Scholar 

  16. 16. Ninomiya-Tsuji J, Nomoto S, Yasuda H, Reed SI, Matsumoto K. Cloning of a human cDNA encoding a CDC2-related kinase by complementation of a budding yeast cdc28 mutation. Proc Natl Acad Sci USA 1991;88:9006–9010.

    Article  PubMed  CAS  Google Scholar 

  17. 17. Meyerson M, Enders GH, Wu CL, et al. A family of human cdc2-related protein kinases. Embo J 1992;11:2909–2917.

    PubMed  CAS  Google Scholar 

  18. 18. Matsushime H, Ewen ME, Strom DK, et al. Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 1992;71:323–334.

    Article  PubMed  CAS  Google Scholar 

  19. 19. Xiong Y, Zhang H, Beach D. D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 1992;71:505–514.

    Article  PubMed  CAS  Google Scholar 

  20. 20. Hellmich MR, Pant HC, Wada E, Battey JF. Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression. Proc Natl Acad Sci USA 1992;89: 10867–10871.

    Article  PubMed  CAS  Google Scholar 

  21. 21. Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci 2005;30:630–641.

    Article  PubMed  CAS  Google Scholar 

  22. 22. Fisher RP, Morgan DO. A novel cyclin associates with MO15/CDK7 to form the CDK-activating kinase. Cell 1994;78:713–724.

    Article  PubMed  CAS  Google Scholar 

  23. 23. Tassan JP, Jaquenoud M, Leopold P, Schultz SJ, Nigg EA. Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C. Proc Natl Acad Sci USA 1995;92:8871–8875.

    Article  PubMed  CAS  Google Scholar 

  24. 24. Grana X, De Luca A, Sang N, et al. PITALRE, a nuclear CDC2-related protein kinase that phosphorylates the retinoblastoma protein in vitro. Proc Natl Acad Sci USA 1994;91:3834–3838.

    Article  PubMed  CAS  Google Scholar 

  25. 25. Grana X, Claudio PP, De Luca A, Sang N, Giordano A. PISSLRE, a human novel CDC2-related protein kinase. Oncogene 1994;9:2097–2103.

    PubMed  CAS  Google Scholar 

  26. 26. Xiang J, Lahti JM, Grenet J, Easton J, Kidd VJ. Molecular cloning and expression of alternatively spliced PITSLRE protein kinase isoforms. J Biol Chem 1994;269:15786–15794.

    PubMed  CAS  Google Scholar 

  27. 27. Chen HH, Wang YC, Fann MJ. Identification and characterization of the CDK12/cyclin L1 complex involved in alternative splicing regulation. Mol Cell Biol 2006;26:2736–2745.

    Article  PubMed  CAS  Google Scholar 

  28. 28. Kesavapany S, Li BS, Amin N, Zheng YL, Grant P, Pant HC. Neuronal cyclin-dependent kinase 5: role in nervous system function and its specific inhibition by the Cdk5 inhibitory peptide. Biochim Biophys Acta 2004;1697:143–153.

    PubMed  CAS  Google Scholar 

  29. 29. Cruz JC, Tsai LH. A Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease. Curr Opin Neurobiol 2004;14:390–394.

    Article  PubMed  CAS  Google Scholar 

  30. 30. Fisher RP. Secrets of a double agent: CDK7 in cell-cycle control and transcription. J Cell Sci 2005;118:5171–5180.

    Article  PubMed  CAS  Google Scholar 

  31. 31. Sano M, Schneider MD. Cyclins that don't cycle–cyclin T/cyclin-dependent kinase-9 determines cardiac muscle cell size. Cell Cycle 2003;2:99–104.

    Article  PubMed  CAS  Google Scholar 

  32. 32. Garriga J, Grana X. Cellular control of gene expression by T-type cyclin/CDK9 complexes. Gene 2004;337:15–23.

    Article  PubMed  CAS  Google Scholar 

  33. 33. Kasten M, Giordano A. Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity. Oncogene 2001;20:1832–1838.

    Article  PubMed  CAS  Google Scholar 

  34. 34. Bagella L, Giacinti C, Simone C, Giordano A. Identification of murine cdk10: association with Ets2 transcription factor and effects on the cell cycle. J Cell Biochem 2006;99:978–985.

    Article  PubMed  CAS  Google Scholar 

  35. 35. Hu D, Mayeda A, Trembley JH, Lahti JM, Kidd VJ. CDK11 complexes promote pre-mRNA splicing. J Biol Chem 2003;278:8623–8629.

    Article  PubMed  CAS  Google Scholar 

  36. 36. Petretti C, Savoian M, Montembault E, Glover DM, Prigent C, Giet R. The PITSLRE/CDK11p58 protein kinase promotes centrosome maturation and bipolar spindle formation. EMBO Rep 2006;7:418–424.

    PubMed  CAS  Google Scholar 

  37. 37. Loyer P, Trembley JH, Katona R, Kidd VJ, Lahti JM. Role of CDK/cyclin complexes in transcription and RNA splicing. Cell Signal 2005;17:1033–1051.

    Article  PubMed  CAS  Google Scholar 

  38. 38. Giordano A, Whyte P, Harlow E, Franza BR, Jr., Beach D, Draetta G. A 60 kd cdc2-associated polypeptide complexes with the E1A proteins in adenovirus-infected cells. Cell 1989;58:981–990.

    Article  PubMed  CAS  Google Scholar 

  39. 39. Pines J, Hunter T. Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2. Cell 1989;58:833–846.

    Article  PubMed  CAS  Google Scholar 

  40. 40. Nguyen TB, Manova K, Capodieci P, et al. Characterization and expression of mammalian cyclin b3, a prepachytene meiotic cyclin. J Biol Chem 2002;277:41960–41969.

    Article  PubMed  CAS  Google Scholar 

  41. 41. Ren S, Rollins BJ. Cyclin C/cdk3 promotes Rb-dependent G0 exit. Cell 2004;117:239–251.

    Article  PubMed  CAS  Google Scholar 

  42. 42. Kolonin MG, Finley RL, Jr. A role for cyclin J in the rapid nuclear division cycles of early Drosophila embryogenesis. Dev Biol 2000;227:661–672.

    Article  PubMed  CAS  Google Scholar 

  43. 43. Bai C, Richman R, Elledge SJ. Human cyclin F. Embo J 1994;13:6087–6098.

    PubMed  CAS  Google Scholar 

  44. 44. Kong M, Barnes EA, Ollendorff V, Donoghue DJ. Cyclin F regulates the nuclear localization of cyclin B1 through a cyclin-cyclin interaction. Embo J 2000;19:1378–1388.

    Article  PubMed  CAS  Google Scholar 

  45. 45. Tetzlaff MT, Bai C, Finegold M, et al. Cyclin F disruption compromises placental development and affects normal cell cycle execution. Mol Cell Biol 2004;24:2487–2498.

    Article  PubMed  CAS  Google Scholar 

  46. 46. Chen X. Cyclin G: a regulator of the p53-Mdm2 network. Dev Cell 2002;2:518–519.

    Article  PubMed  CAS  Google Scholar 

  47. 47. Nakamura T, Sanokawa R, Sasaki YF, Ayusawa D, Oishi M, Mori N. Cyclin I: a new cyclin encoded by a gene isolated from human brain. Exp Cell Res 1995;221:534–542.

    Article  PubMed  CAS  Google Scholar 

  48. 48. Matsuoka M, Matsuura Y, Semba K, Nishimoto I. Molecular cloning of a cyclin-like protein associated with cyclin-dependent kinase 3 (cdk 3) in vivo. Biochem Biophys Res Commun 2000;273:442–447.

    Article  PubMed  CAS  Google Scholar 

  49. 49. Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994;264:436–440.

    Article  PubMed  CAS  Google Scholar 

  50. 50. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993;366:704–707.

    Article  PubMed  CAS  Google Scholar 

  51. 51. Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 1994;371:257–261.

    Article  PubMed  CAS  Google Scholar 

  52. 52. Guan KL, Jenkins CW, Li Y, et al. Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev 1994;8:2939–2952.

    Article  PubMed  CAS  Google Scholar 

  53. 53. Hirai H, Roussel MF, Kato JY, Ashmun RA, Sherr CJ. Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol Cell Biol 1995;15:2672–2681.

    PubMed  CAS  Google Scholar 

  54. 54. Chan FK, Zhang J, Cheng L, Shapiro DN, Winoto A. Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4. Mol Cell Biol 1995;15:2682–2688.

    PubMed  CAS  Google Scholar 

  55. 55. Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 1995;83:993–1000.

    Article  PubMed  CAS  Google Scholar 

  56. 56. Gil J, Peters G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 2006;7:667–677.

    Article  PubMed  CAS  Google Scholar 

  57. 57. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999;13:1501–1512.

    Article  PubMed  CAS  Google Scholar 

  58. 58. Sherr CJ. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res 2000;60:3689–3695.

    PubMed  CAS  Google Scholar 

  59. 59. Pavletich NP. Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J Mol Biol 1999;287:821–828.

    Article  PubMed  CAS  Google Scholar 

  60. 60. Russo AA, Tong L, Lee JO, Jeffrey PD, Pavletich NP. Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. Nature 1998;395:237–243.

    Article  PubMed  CAS  Google Scholar 

  61. 61. Brotherton DH, Dhanaraj V, Wick S, et al. Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d. Nature 1998;395:244–250.

    Article  PubMed  CAS  Google Scholar 

  62. 62. Reynisdottir I, Polyak K, Iavarone A, Massague J. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev 1995;9:1831–1845.

    Article  PubMed  CAS  Google Scholar 

  63. 63. Jiang H, Chou HS, Zhu L. Requirement of cyclin E-Cdk2 inhibition in p16(INK4a)-mediated growth suppression. Mol Cell Biol 1998;18:5284–5290.

    PubMed  CAS  Google Scholar 

  64. 64. Zindy F, Quelle DE, Roussel MF, Sherr CJ. Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 1997;15:203–211.

    Article  PubMed  CAS  Google Scholar 

  65. 65. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997;88:593–602.

    Article  PubMed  CAS  Google Scholar 

  66. 66. Malumbres M, Perez De Castro I, Hernandez MI, Jimenez M, Corral T, Pellicer A. Cellular response to oncogenic ras involves induction of the Cdk4 and Cdk6 inhibitor p15(INK4b). Mol Cell Biol 2000;20:2915–2925.

    Article  PubMed  CAS  Google Scholar 

  67. 67. Krishnamurthy J, Ramsey MR, Ligon KL, et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 2006;443:453–457.

    Article  PubMed  CAS  Google Scholar 

  68. 68. Molofsky AV, Slutsky SG, Joseph NM, et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 2006;443:448–452.

    Article  PubMed  CAS  Google Scholar 

  69. 69. Janzen V, Forkert R, Fleming HE, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 2006;443:421–426.

    PubMed  CAS  Google Scholar 

  70. 70. Hengst L, Reed SI. Inhibitors of the Cip/Kip family. Curr Top Microbiol Immunol 1998;227:25–41.

    PubMed  CAS  Google Scholar 

  71. 71. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 1995;9:1149–1163.

    Article  PubMed  CAS  Google Scholar 

  72. 72. Polyak K, Lee MH, Erdjument-Bromage H, et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 1994;78:59–66.

    Article  PubMed  CAS  Google Scholar 

  73. 73. Toyoshima H, Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 1994;78:67–74.

    Article  PubMed  CAS  Google Scholar 

  74. 74. Coqueret O. New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol 2003;13:65–70.

    Article  PubMed  CAS  Google Scholar 

  75. 75. Lee MH, Reynisdottir I, Massague J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev 1995;9:639–649.

    Article  PubMed  CAS  Google Scholar 

  76. 76. Swanger WJ, Roberts JM. p57KIP2 targeted disruption and Beckwith-Wiedemann syndrome: is the inhibitor just a contributor? Bioessays 1997;19:839–842.

    Article  PubMed  CAS  Google Scholar 

  77. 77. Nho RS, Sheaff RJ. p27kip1 contributions to cancer. Prog Cell Cycle Res 2003;5:249–259.

    PubMed  Google Scholar 

  78. 78. Bloom J, Pagano M. Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Semin Cancer Biol 2003;13:41–47.

    Article  PubMed  CAS  Google Scholar 

  79. 79. Russo AA, Jeffrey PD, Patten AK, Massague J, Pavletich NP. Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature 1996;382:325–331.

    Article  PubMed  CAS  Google Scholar 

  80. 80. LaBaer J, Garrett MD, Stevenson LF, et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev 1997;11:847–862.

    Article  PubMed  CAS  Google Scholar 

  81. 81. Bagui TK, Jackson RJ, Agrawal D, Pledger WJ. Analysis of cyclin D3-cdk4 complexes in fibroblasts expressing and lacking p27(kip1) and p21(cip1). Mol Cell Biol 2000;20:8748–8757.

    Article  PubMed  CAS  Google Scholar 

  82. 82. Bagui TK, Mohapatra S, Haura E, Pledger WJ. P27Kip1 and p21Cip1 are not required for the formation of active D cyclin-cdk4 complexes. Mol Cell Biol 2003;23:7285–7290.

    Article  PubMed  CAS  Google Scholar 

  83. 83. Sugimoto M, Martin N, Wilks DP, et al. Activation of cyclin D1-kinase in murine fibroblasts lacking both p21(Cip1) and p27(Kip1). Oncogene 2002;21:8067–8074.

    Article  PubMed  CAS  Google Scholar 

  84. 84. Jeffrey PD, Russo AA, Polyak K, et al. Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature 1995;376:313–320.

    Article  PubMed  CAS  Google Scholar 

  85. 85. Schulze-Gahmen U, Brandsen J, Jones HD, et al. Multiple modes of ligand recognition: crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine. Proteins 1995;22:378–391.

    Article  PubMed  CAS  Google Scholar 

  86. 86. De Bondt HL, Rosenblatt J, Jancarik J, Jones HD, Morgan DO, Kim SH. Crystal structure of cyclin-dependent kinase 2. Nature 1993;363:595–602.

    Article  PubMed  CAS  Google Scholar 

  87. 87. Russo AA, Jeffrey PD, Pavletich NP. Structural basis of cyclin-dependent kinase activation by phosphorylation. Nat Struct Biol 1996;3:696–700.

    Article  PubMed  CAS  Google Scholar 

  88. 88. Bartek J, Lukas C, Lukas J. Checking on DNA damage in S phase. Nat Rev Mol Cell Biol 2004;5:792–804.

    Article  PubMed  CAS  Google Scholar 

  89. 89. Lolli G, Johnson LN. CAK-cyclin-dependent activating kinase: a key kinase in cell cycle control and a target for drugs? Cell Cycle 2005;4:572–577.

    Article  PubMed  CAS  Google Scholar 

  90. 90. Glotzer M, Murray AW, Kirschner MW. Cyclin is degraded by the ubiquitin pathway. Nature 1991;349:132–138.

    Article  PubMed  CAS  Google Scholar 

  91. 91. Clurman BE, Sheaff RJ, Thress K, Groudine M, Roberts JM. Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation. Genes Dev 1996;10:1979–1990.

    Article  PubMed  CAS  Google Scholar 

  92. 92. Diehl JA, Zindy F, Sherr CJ. Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes Dev 1997;11:957–972.

    Article  PubMed  CAS  Google Scholar 

  93. 93. Pines J, Hunter T. Human cyclins A and B1 are differentially located in the cell and undergo cell cycle-dependent nuclear transport. J Cell Biol 1991;115:1–17.

    Article  PubMed  CAS  Google Scholar 

  94. 94. Pines J, Hunter T. The differential localization of human cyclins A and B is due to a cytoplasmic retention signal in cyclin B. Embo J 1994;13:3772–3781.

    PubMed  CAS  Google Scholar 

  95. 95. Jackman M, Kubota Y, den Elzen N, Hagting A, Pines J. Cyclin A- and cyclin E-Cdk complexes shuttle between the nucleus and the cytoplasm. Mol Biol Cell 2002;13:1030–1045.

    Article  PubMed  CAS  Google Scholar 

  96. 96. Besson A, Gurian-West M, Chen X, Kelly-Spratt KS, Kemp CJ, Roberts JM. A pathway in quiescent cells that controls p27Kip1 stability, subcellular localization, and tumor suppression. Genes Dev 2006;20:47–64.

    Article  PubMed  CAS  Google Scholar 

  97. 97. Nilsson K, Landberg G. Subcellular localization, modification and protein complex formation of the cdk-inhibitor p16 in Rb-functional and Rb-inactivated tumor cells. Int J Cancer 2006;118:1120–1125.

    Article  PubMed  CAS  Google Scholar 

  98. 98. Gerber MR, Farrell A, Deshaies RJ, Herskowitz I, Morgan DO. Cdc37 is required for association of the protein kinase Cdc28 with G1 and mitotic cyclins. Proc Natl Acad Sci USA 1995;92:4651–4655.

    Article  PubMed  CAS  Google Scholar 

  99. 99. Stepanova L, Leng X, Parker SB, Harper JW. Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev 1996;10:1491–1502.

    Article  PubMed  CAS  Google Scholar 

  100. 100. Dai K, Kobayashi R, Beach D. Physical interaction of mammalian CDC37 with CDK4. J Biol Chem 1996;271:22030–22034.

    Article  PubMed  CAS  Google Scholar 

  101. 101. Sugimoto M, Nakamura T, Ohtani N, et al. Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1). Genes Dev 1999;13:3027–3033.

    Article  PubMed  CAS  Google Scholar 

  102. 102. Ye X, Zhu C, Harper JW. A premature-termination mutation in the Mus musculus cyclin-dependent kinase 3 gene. Proc Natl Acad Sci USA 2001;98:1682–1686.

    Article  PubMed  CAS  Google Scholar 

  103. 103. Matsushime H, Roussel MF, Ashmun RA, Sherr CJ. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 1991;65:701–713.

    Article  PubMed  CAS  Google Scholar 

  104. 104. Malumbres M, Pellicer A. RAS pathways to cell cycle control and cell transformation. Front Biosci 1998;3:d887–912.

    PubMed  CAS  Google Scholar 

  105. 105. Ciemerych MA, Kenney AM, Sicinska E, et al. Development of mice expressing a single D-type cyclin. Genes Dev 2002;16:3277–3289.

    Article  PubMed  CAS  Google Scholar 

  106. 106. Dyson N. The regulation of E2F by pRB-family proteins. Genes Dev 1998;12:2245–2262.

    Article  PubMed  CAS  Google Scholar 

  107. 107. Harbour JW, Dean DC. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev 2000;14:2393–2409.

    Article  PubMed  CAS  Google Scholar 

  108. 108. Hofmann F, Livingston DM. Differential effects of cdk2 and cdk3 on the control of pRb and E2F function during G1 exit. Genes Dev 1996;10:851–861.

    Article  PubMed  CAS  Google Scholar 

  109. 109. Petersen BO, Lukas J, Sorensen CS, Bartek J, Helin K. Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization. Embo J 1999;18:396–410.

    Article  PubMed  CAS  Google Scholar 

  110. 110. Deans AJ, Khanna KK, McNees CJ, Mercurio C, Heierhorst J, McArthur GA. Cyclin-Dependent Kinase 2 Functions in Normal DNA Repair and Is a Therapeutic Target in BRCA1-Deficient Cancers. Cancer Res 2006;66:8219–8226.

    Article  PubMed  CAS  Google Scholar 

  111. 111. Hayami R, Sato K, Wu W, et al. Down-regulation of BRCA1-BARD1 ubiquitin ligase by CDK2. Cancer Res 2005;65:6–10.

    PubMed  CAS  Google Scholar 

  112. 112. Esashi F, Christ N, Gannon J, et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 2005;434:598–604.

    Article  PubMed  CAS  Google Scholar 

  113. 113. Diederichs S, Baumer N, Ji P, et al. Identification of interaction partners and substrates of the cyclin A1-CDK2 complex. J Biol Chem 2004;279:33727–33741.

    Article  PubMed  CAS  Google Scholar 

  114. 114. Ortega S, Prieto I, Odajima J, et al. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 2003;35:25–31.

    Article  PubMed  CAS  Google Scholar 

  115. 115. Huang H, Regan KM, Lou Z, Chen J, Tindall DJ. CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science 2006;314:294–297.

    Article  PubMed  CAS  Google Scholar 

  116. 116. Nigg EA. Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol 2001;2:21–32.

    Article  PubMed  CAS  Google Scholar 

  117. 117. Peters JM. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 2006; 7:644–656.

    Article  PubMed  CAS  Google Scholar 

  118. 118. Nakayama KI, Nakayama K. Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 2006;6:369–381.

    Article  PubMed  CAS  Google Scholar 

  119. 119. Potapova TA, Daum JR, Pittman BD, et al. The reversibility of mitotic exit in vertebrate cells. Nature 2006;440:954–958.

    Article  PubMed  CAS  Google Scholar 

  120. 120. Li S, MacLachlan TK, De Luca A, Claudio PP, Condorelli G, Giordano A. The cdc-2-related kinase, PISSLRE, is essential for cell growth and acts in G2 phase of the cell cycle. Cancer Res 1995;55:3992–3995.

    PubMed  CAS  Google Scholar 

  121. 121. Cornelis S, Bruynooghe Y, Denecker G, Van Huffel S, Tinton S, Beyaert R. Identification and characterization of a novel cell cycle-regulated internal ribosome entry site. Mol Cell 2000;5:597–605.

    Article  PubMed  CAS  Google Scholar 

  122. 122. Xiang J, Lahti JM, Kidd VJ. 2-Aminopurine overrides a late telophase delay created by ectopic expression of the PITSLRE beta 1 protein kinase. Biochem Biophys Res Commun 1994;199:1167–1173.

    Article  PubMed  CAS  Google Scholar 

  123. 123. Li T, Inoue A, Lahti JM, Kidd VJ. Failure to proliferate and mitotic arrest of CDK11(p110/p58)-null mutant mice at the blastocyst stage of embryonic cell development. Mol Cell Biol 2004;24:3188–3197.

    Article  PubMed  CAS  Google Scholar 

  124. 124. He J, Allen JR, Collins VP, et al. CDK4 amplification is an alternative mechanism to p16 gene homozygous deletion in glioma cell lines. Cancer Res 1994;54:5804–5807.

    PubMed  CAS  Google Scholar 

  125. 125. Sonoda Y, Yoshimoto T, Sekiya T. Homozygous deletion of the MTS1/p16 and MTS2/p15 genes and amplification of the CDK4 gene in glioma. Oncogene 1995;11:2145–2149.

    PubMed  CAS  Google Scholar 

  126. 126. Schmidt EE, Ichimura K, Reifenberger G, Collins VP. CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res 1994;54:6321–6324.

    PubMed  CAS  Google Scholar 

  127. 127. Kanoe H, Nakayama T, Murakami H, et al. Amplification of the CDK4 gene in sarcomas: tumor specificity and relationship with the RB gene mutation. Anticancer Res 1998;18:2317–2321.

    PubMed  CAS  Google Scholar 

  128. 128. Wei G, Lonardo F, Ueda T, et al. CDK4 gene amplification in osteosarcoma: reciprocal relationship with INK4A gene alterations and mapping of 12q13 amplicons. Int J Cancer 1999;80:199–204.

    Article  PubMed  CAS  Google Scholar 

  129. 129. Ragazzini P, Gamberi G, Pazzaglia L, et al. Amplification of CDK4, MDM2, SAS and GLI genes in leiomyosarcoma, alveolar and embryonal rhabdomyosarcoma. Histol Histopathol 2004;19:401–411.

    PubMed  CAS  Google Scholar 

  130. 130. Khatib ZA, Matsushime H, Valentine M, Shapiro DN, Sherr CJ, Look AT. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res 1993;53:5535–5541.

    PubMed  CAS  Google Scholar 

  131. 131. Wunder JS, Eppert K, Burrow SR, Gokgoz N, Bell RS, Andrulis IL. Co-amplification and overexpression of CDK4, SAS and MDM2 occurs frequently in human parosteal osteosarcomas. Oncogene 1999;18:783–788.

    Article  PubMed  CAS  Google Scholar 

  132. 132. Biernat W, Debiec-Rychter M, Liberski PP. Mutations of TP53, amplification of EGFR, MDM2 and CDK4, and deletions of CDKN2A in malignant astrocytomas. Pol J Pathol 1998;49:267–271.

    PubMed  CAS  Google Scholar 

  133. 133. An HX, Beckmann MW, Reifenberger G, Bender HG, Niederacher D. Gene amplification and overexpression of CDK4 in sporadic breast carcinomas is associated with high tumor cell proliferation. Am J Pathol 1999;154:113–118.

    Article  PubMed  CAS  Google Scholar 

  134. 134. Cheung TH, Yu MM, Lo KW, Yim SF, Chung TK, Wong YF. Alteration of cyclin D1 and CDK4 gene in carcinoma of uterine cervix. Cancer Lett 2001;166:199–206.

    Article  PubMed  CAS  Google Scholar 

  135. 135. Wolfel T, Hauer M, Schneider J, et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 1995;269:1281–1284.

    Article  PubMed  CAS  Google Scholar 

  136. 136. Zuo L, Weger J, Yang Q, et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 1996;12:97–99.

    Article  PubMed  CAS  Google Scholar 

  137. 137. Ruano Y, Mollejo M, Ribalta T, et al. Identification of novel candidate target genes in amplicons of Glioblastoma multiforme tumors detected by expression and CGH microarray profiling. Mol Cancer 2006;5:39.

    Article  PubMed  CAS  Google Scholar 

  138. 138. Zhao X, Weir BA, LaFramboise T, et al. Homozygous deletions and chromosome amplifications in human lung carcinomas revealed by single nucleotide polymorphism array analysis. Cancer Res 2005;65:5561–5570.

    Article  PubMed  CAS  Google Scholar 

  139. 139. Hayette S, Tigaud I, Callet-Bauchu E, et al. In B-cell chronic lymphocytic leukemias, 7q21 translocations lead to overexpression of the CDK6 gene. Blood 2003;102:1549–1550.

    Article  PubMed  CAS  Google Scholar 

  140. 140. Brito-Babapulle V, Gruszka-Westwood AM, Platt G, et al. Translocation t(2;7)(p12;q21–22) with dysregulation of the CDK6 gene mapping to 7q21–22 in a non-Hodgkin's lymphoma with leukemia. Haematologica 2002;87:357–362.

    PubMed  CAS  Google Scholar 

  141. 141. Okamoto I, Pirker C, Bilban M, et al. Seven novel and stable translocations associated with oncogenic gene expression in malignant melanoma. Neoplasia 2005;7:303–311.

    Article  PubMed  CAS  Google Scholar 

  142. 142. Kannan K, Sharpless NE, Xu J, O'Hagan RC, Bosenberg M, Chin L. Components of the Rb pathway are critical targets of UV mutagenesis in a murine melanoma model. Proc Natl Acad Sci USA 2003;100:1221–1225.

    Article  PubMed  CAS  Google Scholar 

  143. 143. Mendrzyk F, Radlwimmer B, Joos S, et al. Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma. J Clin Oncol 2005;23:8853–8862.

    Article  PubMed  CAS  Google Scholar 

  144. 144. Ito Y, Takeda T, Sakon M, Monden M, Tsujimoto M, Matsuura N. Expression and prognostic role of cyclin-dependent kinase 1 (cdc2) in hepatocellular carcinoma. Oncology 2000;59:68–74.

    Article  PubMed  CAS  Google Scholar 

  145. 145. Yamamoto H, Monden T, Miyoshi H, et al. Cdk2/cdc2 expression in colon carcinogenesis and effects of cdk2/cdc2 inhibitor in colon cancer cells. Int J Oncol 1998;13:233–239.

    PubMed  CAS  Google Scholar 

  146. 146. Barrette BA, Srivatsa PJ, Cliby WA, et al. Overexpression of p34cdc2 protein kinase in epithelial ovarian carcinoma. Mayo Clin Proc 1997;72:925–929.

    Article  PubMed  CAS  Google Scholar 

  147. 147. Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z. A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 2006;38:1043–1048.

    Article  PubMed  CAS  Google Scholar 

  148. 148. Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 2001;1:222–231.

    Article  PubMed  CAS  Google Scholar 

  149. 149. Ruas M, Peters G. The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta 1998;1378:F115–177.

    PubMed  CAS  Google Scholar 

  150. 150. Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta 2002;1602:73–87.

    PubMed  CAS  Google Scholar 

  151. 151. Motokura T, Bloom T, Kim HG, et al. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 1991;350: 512–515.

    Article  PubMed  CAS  Google Scholar 

  152. 152. Rosenberg CL, Wong E, Petty EM, et al. PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma. Proc Natl Acad Sci USA 1991;88:9638–9642.

    Article  PubMed  CAS  Google Scholar 

  153. 153. Withers DA, Harvey RC, Faust JB, Melnyk O, Carey K, Meeker TC. Characterization of a candidate bcl-1 gene. Mol Cell Biol 1991;11:4846–4853.

    PubMed  CAS  Google Scholar 

  154. 154. Hosokawa Y, Arnold A. Mechanism of cyclin D1 (CCND1, PRAD1) overexpression in human cancer cells: analysis of allele-specific expression. Genes Chromosomes Cancer 1998;22:66–71.

    Article  PubMed  CAS  Google Scholar 

  155. 155. Lammie GA, Fantl V, Smith R, et al. D11S287, a putative oncogene on chromosome 11q13, is amplified and expressed in squamous cell and mammary carcinomas and linked to BCL-1. Oncogene 1991;6:439–444.

    PubMed  CAS  Google Scholar 

  156. 156. Leach FS, Elledge SJ, Sherr CJ, et al. Amplification of cyclin genes in colorectal carcinomas. Cancer Res 1993;53:1986–1989.

    PubMed  CAS  Google Scholar 

  157. 157. Keyomarsi K, Pardee AB. Redundant cyclin overexpression and gene amplification in breast cancer cells. Proc Natl Acad Sci USA 1993;90:1112–1116.

    Article  PubMed  CAS  Google Scholar 

  158. 158. Barbareschi M, Pelosio P, Caffo O, et al. Cyclin-D1-gene amplification and expression in breast carcinoma: relation with clinicopathologic characteristics and with retinoblastoma gene product, p53 and p21WAF1 immunohistochemical expression. Int J Cancer 1997;74:171–174.

    Article  PubMed  CAS  Google Scholar 

  159. 159. Frierson HF, Jr., Gaffey MJ, Zukerberg LR, Arnold A, Williams ME. Immunohistochemical detection and gene amplification of cyclin D1 in mammary infiltrating ductal carcinoma. Mod Pathol 1996;9:725–730.

    PubMed  Google Scholar 

  160. 160. Diehl JA. Cycling to cancer with cyclin D1. Cancer Biol Ther 2002;1:226–231.

    PubMed  CAS  Google Scholar 

  161. 161. Donnellan R, Chetty R. Cyclin D1 and human neoplasia. Mol Pathol 1998;51:1–7.

    Article  PubMed  CAS  Google Scholar 

  162. 162. Delmer A, Ajchenbaum-Cymbalista F, Tang R, et al. Overexpression of cyclin D2 in chronic B-cell malignancies. Blood 1995;85:2870–2876.

    PubMed  CAS  Google Scholar 

  163. 163. Buschges R, Weber RG, Actor B, Lichter P, Collins VP, Reifenberger G. Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) in human malignant gliomas. Brain Pathol 1999;9:435–442; discussion –433.

    Article  PubMed  CAS  Google Scholar 

  164. 164. Takano Y, Kato Y, Masuda M, Ohshima Y, Okayasu I. Cyclin D2, but not cyclin D1, overexpression closely correlates with gastric cancer progression and prognosis. J Pathol 1999;189:194–200.

    Article  PubMed  CAS  Google Scholar 

  165. 165. Liu SC, Bassi DE, Zhang SY, Holoran D, Conti CJ, Klein-Szanto AJ. Overexpression of cyclin D2 is associated with increased in vivo invasiveness of human squamous carcinoma cells. Mol Carcinog 2002;34:131–139.

    Article  PubMed  CAS  Google Scholar 

  166. 166. Bartkova J, Lukas C, Sorensen CS, et al. Deregulation of the RB pathway in human testicular germ cell tumours. J Pathol 2003;200:149–156.

    Article  PubMed  CAS  Google Scholar 

  167. 167. Clappier E, Cuccuini W, Cayuela JM, et al. Cyclin D2 dysregulation by chromosomal translocations to TCR loci in T-cell acute lymphoblastic leukemias. Leukemia 2006;20:82–86.

    Article  PubMed  CAS  Google Scholar 

  168. 168. Moller MB, Nielsen O, Pedersen NT. Cyclin D3 expression in non-Hodgkin lymphoma. Correlation with other cell cycle regulators and clinical features. Am J Clin Pathol 2001;115:404–412.

    Article  PubMed  CAS  Google Scholar 

  169. 169. Sonoki T, Harder L, Horsman DE, et al. Cyclin D3 is a target gene of t(6;14)(p21.1;q32.3) of mature B-cell malignancies. Blood 2001;98:2837–2844.

    Article  PubMed  CAS  Google Scholar 

  170. 170. Bondi J, Husdal A, Bukholm G, Nesland JM, Bakka A, Bukholm IR. Expression and gene amplification of primary (A, B1, D1, D3, and E) and secondary (C and H) cyclins in colon adenocarcinomas and correlation with patient outcome. J Clin Pathol 2005;58:509–514.

    Article  PubMed  CAS  Google Scholar 

  171. 171. Lopez-Beltran A, Requena MJ, Luque RJ, et al. Cyclin D3 expression in primary Ta/T1 bladder cancer. J Pathol 2006;209:106–113.

    Article  PubMed  CAS  Google Scholar 

  172. 172. Gladden AB, Diehl JA. Location, location, location: the role of cyclin D1 nuclear localization in cancer. J Cell Biochem 2005;96:906–913.

    Article  PubMed  CAS  Google Scholar 

  173. 173. Van Dross R, Browning PJ, Pelling JC. Do truncated cyclins contribute to aberrant cyclin expression in cancer? Cell Cycle 2006;5:472–477.

    Article  PubMed  Google Scholar 

  174. 174. Akli S, Keyomarsi K. Cyclin E and its low molecular weight forms in human cancer and as targets for cancer therapy. Cancer Biol Ther 2003;2:S38–47.

    PubMed  CAS  Google Scholar 

  175. 175. Hwang HC, Clurman BE. Cyclin E in normal and neoplastic cell cycles. Oncogene 2005;24:2776–2786.

    Article  PubMed  CAS  Google Scholar 

  176. 176. Erlanson M, Landberg G. Prognostic implications of p27 and cyclin E protein contents in malignant lymphomas. Leuk Lymphoma 2001;40:461–470.

    Article  PubMed  CAS  Google Scholar 

  177. 177. Hunt KK, Keyomarsi K. Cyclin E as a prognostic and predictive marker in breast cancer. Semin Cancer Biol 2005;15:319–326.

    Article  PubMed  CAS  Google Scholar 

  178. 178. Donnellan R, Chetty R. Cyclin E in human cancers. Faseb J 1999;13:773–780.

    PubMed  CAS  Google Scholar 

  179. 179. Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 1994;368:753–756.

    Article  PubMed  CAS  Google Scholar 

  180. 180. Hussussian CJ, Struewing JP, Goldstein AM, et al. Germline p16 mutations in familial melanoma. Nat Genet 1994;8:15–21.

    Article  PubMed  CAS  Google Scholar 

  181. 181. Kamb A, Shattuck-Eidens D, Eeles R, et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet 1994;8:23–26.

    Article  PubMed  CAS  Google Scholar 

  182. 182. Quelle DE, Cheng M, Ashmun RA, Sherr CJ. Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF. Proc Natl Acad Sci USA 1997;94:669–673.

    Article  PubMed  CAS  Google Scholar 

  183. 183. Hirama T, Koeffler HP. Role of the cyclin-dependent kinase inhibitors in the development of cancer. Blood 1995;86:841–854.

    PubMed  CAS  Google Scholar 

  184. 184. Herman JG, Jen J, Merlo A, Baylin SB. Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res 1996;56:722–727.

    PubMed  CAS  Google Scholar 

  185. 185. Batova A, Diccianni MB, Yu JC, et al. Frequent and selective methylation of p15 and deletion of both p15 and p16 in T-cell acute lymphoblastic leukemia. Cancer Res 1997;57:832–836.

    PubMed  CAS  Google Scholar 

  186. 186. Herman JG, Civin CI, Issa JP, Collector MI, Sharkis SJ, Baylin SB. Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res 1997;57:837–841.

    PubMed  CAS  Google Scholar 

  187. 187. Martinez-Delgado B, Robledo M, Arranz E, et al. Hypermethylation of p15/ink4b/MTS2 gene is differentially implicated among non-Hodgkin's lymphomas. Leukemia 1998;12:937–941.

    Article  PubMed  CAS  Google Scholar 

  188. 188. Sanchez-Aguilera A, Delgado J, Camacho FI, et al. Silencing of the p18INK4c gene by promoter hypermethylation in Reed-Sternberg cells in Hodgkin lymphomas. Blood 2004;103:2351–2357.

    Article  PubMed  CAS  Google Scholar 

  189. 189. Bartkova J, Thullberg M, Rajpert-De Meyts E, Skakkebaek NE, Bartek J. Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis. Oncogene 2000;19:4146–4150.

    Article  PubMed  CAS  Google Scholar 

  190. 190. Thompson MA, Stumph J, Henrickson SE, et al. Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas. Hum Pathol 2005;36:494–504.

    Article  PubMed  CAS  Google Scholar 

  191. 191. Zhu WG, Dai Z, Ding H, et al. Increased expression of unmethylated CDKN2D by 5-aza-2′-deoxycytidine in human lung cancer cells. Oncogene 2001;20:7787–7796.

    Article  PubMed  CAS  Google Scholar 

  192. 192. Malumbres M, Carnero A. Cell cycle deregulation: a common motif in cancer. Prog Cell Cycle Res 2003;5:5–18.

    PubMed  Google Scholar 

  193. 193. Loda M, Cukor B, Tam SW, et al. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 1997;3:231–234.

    Article  PubMed  CAS  Google Scholar 

  194. 194. Catzavelos C, Bhattacharya N, Ung YC, et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med 1997;3:227–230.

    Article  PubMed  CAS  Google Scholar 

  195. 195. Porter PL, Malone KE, Heagerty PJ, et al. Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med 1997;3:222–225.

    Article  PubMed  CAS  Google Scholar 

  196. 196. Tsihlias J, Kapusta L, Slingerland J. The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu Rev Med 1999;50:401–423.

    Article  PubMed  CAS  Google Scholar 

  197. 197. Hershko DD, Shapira M. Prognostic role of p27Kip1 deregulation in colorectal cancer. Cancer 2006;107:668–675.

    Article  PubMed  CAS  Google Scholar 

  198. 198. Pagano M, Tam SW, Theodoras AM, et al. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 1995;269:682–685.

    Article  PubMed  CAS  Google Scholar 

  199. 199. Latres E, Chiarle R, Schulman BA, et al. Role of the F-box protein Skp2 in lymphomagenesis. Proc Natl Acad Sci USA 2001;98:2515–2520.

    Article  PubMed  CAS  Google Scholar 

  200. 200. Carrano AC, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1999;1:193–199.

    Article  PubMed  CAS  Google Scholar 

  201. 201. Karlsson-Rosenthal C, Millar JB. Cdc25: mechanisms of checkpoint inhibition and recovery. Trends Cell Biol 2006;16:285–292.

    Article  PubMed  CAS  Google Scholar 

  202. 202. Boutros R, Dozier C, Ducommun B. The when and wheres of CDC25 phosphatases. Curr Opin Cell Biol 2006;18:185–191.

    Article  PubMed  CAS  Google Scholar 

  203. 203. Scambia G, Lovergine S, Masciullo V. RB family members as predictive and prognostic factors in human cancer. Oncogene 2006;25:5302–5308.

    Article  PubMed  CAS  Google Scholar 

  204. 204. Paggi MG, Giordano A. Who is the boss in the retinoblastoma family? The point of view of Rb2/p130, the little brother. Cancer Res 2001;61:4651–4654.

    PubMed  CAS  Google Scholar 

  205. 205. Yamasaki L. Modeling cell cycle control and cancer with pRB tumor suppressor. Results Probl Cell Differ 2006;42:227–256.

    Article  PubMed  CAS  Google Scholar 

  206. 206. Gabellini C, Del Bufalo D, Zupi G. Involvement of RB gene family in tumor angiogenesis. Oncogene 2006;25:5326–5332.

    Article  PubMed  CAS  Google Scholar 

  207. 207. Rane SG, Dubus P, Mettus RV, et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 1999;22:44–52.

    Article  PubMed  CAS  Google Scholar 

  208. 208. Tsutsui T, Hesabi B, Moons DS, et al. Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kip1) activity. Mol Cell Biol 1999;19:7011–7019.

    PubMed  CAS  Google Scholar 

  209. 209. Malumbres M, Sotillo R, Santamaria D, et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 2004;118:493–504.

    Article  PubMed  CAS  Google Scholar 

  210. 210. Martin J, Hunt SL, Dubus P, et al. Genetic rescue of Cdk4 null mice restores pancreatic beta-cell proliferation but not homeostatic cell number. Oncogene 2003;22:5261–5269.

    Article  PubMed  CAS  Google Scholar 

  211. 211. Kozar K, Ciemerych MA, Rebel VI, et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell 2004;118:477–491.

    Article  PubMed  CAS  Google Scholar 

  212. 212. Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P. Cdk2 knockout mice are viable. Curr Biol 2003;13:1775–1785.

    Article  PubMed  CAS  Google Scholar 

  213. 213. Parisi T, Beck AR, Rougier N, et al. Cyclins E1 and E2 are required for endoreplication in placental trophoblast giant cells. Embo J 2003;22:4794–4803.

    Article  PubMed  CAS  Google Scholar 

  214. 214. Geng Y, Yu Q, Sicinska E, et al. Cyclin E ablation in the mouse. Cell 2003;114:431–443.

    Article  PubMed  CAS  Google Scholar 

  215. 215. Tetsu O, McCormick F. Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 2003;3:233–245.

    Article  PubMed  CAS  Google Scholar 

  216. 216. Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 2004;430:226–231.

    Article  PubMed  CAS  Google Scholar 

  217. 217. Ubersax JA, Woodbury EL, Quang PN, et al. Targets of the cyclin-dependent kinase Cdk1. Nature 2003;425:859–864.

    Article  PubMed  CAS  Google Scholar 

  218. 218. Moore JD, Kirk JA, Hunt T. Unmasking the S-phase-promoting potential of cyclin B1. Science 2003;300:987–990.

    Article  PubMed  CAS  Google Scholar 

  219. 219. Ciemerych MA, Sicinski P. Cell cycle in mouse development. Oncogene 2005;24:2877–2898.

    Article  PubMed  CAS  Google Scholar 

  220. 220. Murphy M, Stinnakre MG, Senamaud-Beaufort C, et al. Delayed early embryonic lethality following disruption of the murine cyclin A2 gene. Nat Genet 1997;15:83–86.

    Article  PubMed  CAS  Google Scholar 

  221. 221. Brandeis M, Rosewell I, Carrington M, et al. Cyclin B2-null mice develop normally and are fertile whereas cyclin B1-null mice die in utero. Proc Natl Acad Sci USA 1998;95:4344–4349.

    Article  PubMed  CAS  Google Scholar 

  222. 222. Liu D, Matzuk MM, Sung WK, Guo Q, Wang P, Wolgemuth DJ. Cyclin A1 is required for meiosis in the male mouse. Nat Genet 1998;20:377–380.

    Article  PubMed  CAS  Google Scholar 

  223. 223. Kimura SH, Ikawa M, Ito A, Okabe M, Nojima H. Cyclin G1 is involved in G2/M arrest in response to DNA damage and in growth control after damage recovery. Oncogene 2001;20:3290–3300.

    Article  PubMed  CAS  Google Scholar 

  224. 224. Jensen MR, Factor VM, Fantozzi A, Helin K, Huh CG, Thorgeirsson SS. Reduced hepatic tumor incidence in cyclin G1-deficient mice. Hepatology 2003;37:862–870.

    Article  PubMed  CAS  Google Scholar 

  225. 225. Yan Y, Frisen J, Lee MH, Massague J, Barbacid M. Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. Genes Dev 1997;11:973–983.

    Article  PubMed  CAS  Google Scholar 

  226. 226. Zhang P, Liegeois NJ, Wong C, et al. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature 1997;387:151–158.

    Article  PubMed  CAS  Google Scholar 

  227. 227. Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 1995;377:552–557.

    Article  PubMed  CAS  Google Scholar 

  228. 228. Martin-Caballero J, Flores JM, Garcia-Palencia P, Serrano M. Tumor susceptibility of p21(Waf1/Cip1)-deficient mice. Cancer Res 2001;61:6234–6238.

    PubMed  CAS  Google Scholar 

  229. 229. Fero ML, Rivkin M, Tasch M, et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell 1996;85: 733–744.

    Article  PubMed  CAS  Google Scholar 

  230. 230. Kiyokawa H, Kineman RD, Manova-Todorova KO, et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell 1996;85:721–732.

    Article  PubMed  CAS  Google Scholar 

  231. 231. Nakayama K, Ishida N, Shirane M, et al. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 1996;85:707–720.

    Article  PubMed  CAS  Google Scholar 

  232. 232. Sharpless NE, Bardeesy N, Lee KH, et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 2001;413:86–91.

    Article  PubMed  CAS  Google Scholar 

  233. 233. Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A. Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 2001;413:83–86.

    Article  PubMed  CAS  Google Scholar 

  234. 234. Latres E, Malumbres M, Sotillo R, et al. Limited overlapping roles of P15(INK4b) and P18(INK4c) cell cycle inhibitors in proliferation and tumorigenesis. Embo J 2000;19:3496–3506.

    Article  PubMed  CAS  Google Scholar 

  235. 235. Franklin DS, Godfrey VL, Lee H, et al. CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes Dev 1998;12:2899–2911.

    Article  PubMed  CAS  Google Scholar 

  236. 236. Rane SG, Cosenza SC, Mettus RV, Reddy EP. Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence. Mol Cell Biol 2002;22:644–656.

    Article  PubMed  CAS  Google Scholar 

  237. 237. Sotillo R, Dubus P, Martin J, et al. Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors. Embo J 2001;20:6637–6647.

    Article  PubMed  CAS  Google Scholar 

  238. 238. Sotillo R, Garcia JF, Ortega S, et al. Invasive melanoma in Cdk4-targeted mice. Proc Natl Acad Sci USA 2001;98:13312–13317.

    Article  PubMed  CAS  Google Scholar 

  239. 239. Sotillo R, Renner O, Dubus P, et al. Cooperation between Cdk4 and p27kip1 in tumor development: a preclinical model to evaluate cell cycle inhibitors with therapeutic activity. Cancer Res 2005;65:3846–3852.

    Article  PubMed  CAS  Google Scholar 

  240. 240. Martin A, Odajima J, Hunt SL, et al. Cdk2 is dispensable for cell cycle inhibition and tumor suppression mediated by p27(Kip1) and p21(Cip1). Cancer Cell 2005;7:591–598.

    Article  PubMed  CAS  Google Scholar 

  241. 241. Aleem E, Kiyokawa H, Kaldis P. Cdc2-cyclin E complexes regulate the G1/S phase transition. Nat Cell Biol 2005;7:831–836.

    Article  PubMed  CAS  Google Scholar 

  242. 242. Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW. Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 2006;9:13–22.

    Article  PubMed  CAS  Google Scholar 

  243. 243. Yu Q, Sicinska E, Geng Y, et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 2006;9:23–32.

    Article  PubMed  CAS  Google Scholar 

  244. 244. Reddy HK, Mettus RV, Rane SG, Grana X, Litvin J, Reddy EP. Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis. Cancer Res 2005;65:10174–10178.

    Article  PubMed  CAS  Google Scholar 

  245. 245. Malumbres M, Barbacid M. Is Cyclin D1-CDK4 kinase a bona fide cancer target? Cancer Cell 2006;9:2–4.

    Article  PubMed  CAS  Google Scholar 

  246. 246. Senderowicz AM. Inhibitors of cyclin-dependent kinase modulators for cancer therapy. Prog Drug Res 2005;63:183–206.

    Article  PubMed  CAS  Google Scholar 

  247. 247. Schwartz GK, Shah MA. Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol 2005;23:9408–9421.

    Article  PubMed  CAS  Google Scholar 

  248. 248. Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 2006;24:1770–1783.

    Article  PubMed  CAS  Google Scholar 

  249. 249. Sausville EA. Cell cycle regulatory kinase modulators: interim progress and issues. Curr Top Med Chem 2005;5:1109–1117.

    Article  PubMed  CAS  Google Scholar 

  250. 250. Collins I, Garrett MD. Targeting the cell division cycle in cancer: CDK and cell cycle checkpoint kinase inhibitors. Curr Opin Pharmacol 2005;5:366–373.

    Article  PubMed  CAS  Google Scholar 

  251. 251. Shapiro GI. Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol. Clin Cancer Res 2004;10:4270s–4275s.

    Article  PubMed  CAS  Google Scholar 

  252. 252. Toogood PL, Harvey PJ, Repine JT, et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem 2005;48:2388–2406.

    Article  PubMed  CAS  Google Scholar 

  253. 253. Soni R, O'Reilly T, Furet P, et al. Selective in vivo and in vitro effects of a small molecule inhibitor of cyclin-dependent kinase 4. J Natl Cancer Inst 2001;93:436–446.

    Article  PubMed  CAS  Google Scholar 

  254. 254. Fry DW, Bedford DC, Harvey PH, et al. Cell cycle and biochemical effects of PD 0183812, a potent inhibitor of the cyclin D-dependent kinases CDK 4 and CDK6. J Biol Chem 2001;276:16617–16623.

    Article  PubMed  CAS  Google Scholar 

  255. 255. Soni R, Muller L, Furet P, et al. Inhibition of cyclin-dependent kinase 4 (Cdk4) by fascaplysin, a marine natural product. Biochem Biophys Res Commun 2000;275:877–884.

    Article  PubMed  CAS  Google Scholar 

  256. 256. Honma T, Hayashi K, Aoyama T, et al. Structure-based generation of a new class of potent Cdk4 inhibitors: New design strategy and library design. J Med Chem 2001;44:4615–4627.

    Article  PubMed  CAS  Google Scholar 

  257. 257. Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004;3:1427–1438.

    PubMed  CAS  Google Scholar 

  258. 258. Baughn LB, Di Liberto M, Wu K, et al. A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res 2006;66:7661–7667.

    Article  PubMed  CAS  Google Scholar 

  259. 259. Vulpetti A, Pevarello P. An analysis of the binding modes of ATP-competitive CDK2 inhibitors as revealed by X-ray structures of protein-inhibitor complexes. Curr Med Chem Anticancer Agents 2005;5:561–573.

    Article  PubMed  CAS  Google Scholar 

  260. 260. McClue SJ, Clarke R, Cowan A, et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). IntnatlJ Cancer 2002;102:463–468.

    Article  CAS  Google Scholar 

  261. 261. Misra RN, Xiao Hy, Kim KS, et al. N-(cycloalkylamino) acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl] thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a high-ly efficacious and selective antitumor agent. J Med Chem 2004;47:1719–1728.

    Article  PubMed  CAS  Google Scholar 

  262. Siemeister GB, Brumby H, Haberey M et al. The dual-specific CDK2/VEGF-RTK inhibitor ZK-CDK potently inhibits proliferation of human tumor cells, induces apoptosis, and inhibits growth of human xenograft tumors. Proc Am Assoc Cancer Res; 2004; volume:page (abstract number).

    Google Scholar 

  263. 263. Bach S, Knockaert M, Reinhardt J, et al. Roscovitine targets, protein kinases and pyridoxal kinase. J Biol Chem 2005;280:31208–31219.

    Article  PubMed  CAS  Google Scholar 

  264. 264. Malumbres M. Revisiting the “Cdk-centric” view of the mammalian cell cycle. Cell Cycle 2005;4:206–210.

    Article  PubMed  CAS  Google Scholar 

  265. 265. Kuo GH, DeAngelis A, Emanuel S, et al. Synthesis and identification of [1,3,5]triazine-pyridine biheteroaryl as a novel series of potent cyclin-dependent kinase inhibitors. J Med Chem 2005;48:4535–4546.

    Article  PubMed  CAS  Google Scholar 

  266. 266. Bartkova J, Zemanova M, Bartek J. Expression of CDK7/CAK in normal and tumor cells of diverse histogenesis, cell-cycle position and differentiation. Int J Cancer 1996;66:732–737.

    Article  PubMed  CAS  Google Scholar 

  267. 267. Cai D, Latham VM, Jr., Zhang X, Shapiro GI. Combined depletion of cell cycle and transcriptional cyclin-dependent kinase activities induces apoptosis in cancer cells. Cancer Res 2006;66:9270–9280.

    Article  PubMed  CAS  Google Scholar 

  268. 268. Kallakury BVS, Sheehan CE, Ambros RA, Fisher HAG, Kaufman RP, Ross JS. The prognostic significance of p34cdc2 and cyclin D1 protein expression in prostate adenocarcinoma. Cancer 1997;80:753–763.

    Article  PubMed  CAS  Google Scholar 

  269. 269. Soria J-C, Jang SJ, Khuri FR, et al. Overexpression of cyclin B1 in early-stage non-small cell lung cancer and its clinical implication. Cancer Res 2000;60:4000–4004.

    PubMed  CAS  Google Scholar 

  270. 270. Shinsuke Takeno S, Kikuchi R, Uchida Y, Yokoyama S, Müller W. Prognostic value of cyclin B1 in patients with esophageal squamous cell carcinoma. Cancer 2002;94:2874–2881.

    Article  PubMed  Google Scholar 

  271. 271. L'Italien L, Tanudji M, Russell L, Schebye XM. Unmasking the redundancy between Cdk1 and Cdk2 at G2 phase in human cancer cell lines. Cell Cycle 2006;5:984–993.

    Article  PubMed  Google Scholar 

  272. 272. Brachwitz K, Voigt B, Meijer L, et al. Evaluation of the first cytostatically active 1-aza-9-oxafluorenes as novel selective CDK1 inhibitors with P-glycoprotein modulating properties. J Med Chem 2003;46:876–879.

    Article  PubMed  CAS  Google Scholar 

  273. 273. Cai D, Byth KF, Shapiro GI. AZ703, an imidazo[1,2-a]pyridine inhibitor of cyclin-dependent kinases 1 and 2, induces E2F-1-dependent apoptosis enhanced by depletion of cyclin-dependent kinase 9. Cancer Res 2006;66:435–444.

    Article  PubMed  CAS  Google Scholar 

  274. 274. Vassilev LT, Tovar C, Chen S, et al. Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1. Proc Natl –Sci USA 2006;103:10660–10665.

    Article  CAS  Google Scholar 

  275. 275. McInnes C, Andrews MJ, Zheleva DI, Lane DP, Fischer PM. Peptidomimetic design of CDK inhibitors targeting the recruitment site of the cyclin subunit. Curr Med Chem Anticancer Agents 2003;3:57–69.

    Article  PubMed  CAS  Google Scholar 

  276. 276. Endicott JA, Noble ME, Tucker JA. Cyclin-dependent kinases: inhibition and substrate recognition. Curr Opin Struct Biol 1999;9:738–744.

    Article  PubMed  CAS  Google Scholar 

  277. 277. Zheleva DI, McInnes C, Gavine AL, Zhelev NZ, Fischer PM, Lane DP. Highly potent p21(WAF1)-derived peptide inhibitors of CDK-mediated pRb phosphorylation: delineation and structural insight into their interactions with cyclin A. J Pept Res 2002;60:257–270.

    Article  PubMed  CAS  Google Scholar 

  278. 278. Villacanas O, Perez JJ, Rubio-Martinez J. Structural analysis of the inhibition of Cdk4 and Cdk6 by p16(INK4a) through molecular dynamics simulations. J Biomol Struct Dyn 2002;20:347–358.

    PubMed  CAS  Google Scholar 

  279. 279. Fahraeus R, Lain S, Ball KL, Lane DP. Characterization of the cyclin-dependent kinase inhibitory domain of the INK4 family as a model for a synthetic tumour suppressor molecule. Oncogene 1998;16:587–596.

    Article  PubMed  CAS  Google Scholar 

  280. 280. Fischer PM, Lane DP. Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics. Curr Med Chem 2000;7:1213–1245.

    PubMed  CAS  Google Scholar 

  281. 281. Modesitt SC, Ramirez P, Zu Z, Bodurka-Bevers D, Gershenson D, Wolf JK. In vitro and in vivo adenovirus-mediated p53 and p16 tumor suppressor therapy in ovarian cancer. Clin Cancer Res 2001;7:1765–1772.

    PubMed  CAS  Google Scholar 

  282. 282. Chen F, Li Y, Lu Z, Gao J, Chen J. Adenovirus-mediated Ink4a/ARF gene transfer significantly suppressed the growth of pancreatic carcinoma cells. Cancer Biol Ther 2005;4:1348–1354.

    Article  PubMed  CAS  Google Scholar 

  283. 283. Turturro F, Arnold MD, Frist AY, Seth P. Effects of adenovirus-mediated expression of p27Kip1, p21Waf1 and p16INK4A in cell lines derived from t(2;5) anaplastic large cell lymphoma and Hodgkin's disease. Leuk Lymphoma 2002;43:1323–1328.

    Article  PubMed  CAS  Google Scholar 

  284. 284. Ghaneh P, Greenhalf W, Humphreys M, et al. Adenovirus- mediated transfer of p53 and p16(INK4a) results in pancreatic cancer regression in vitro and in vivo. Gene Ther 2001;8:199–208.

    Article  PubMed  CAS  Google Scholar 

  285. 285. Grim J, D'Amico A, Frizelle S, Zhou J, Kratzke RA, Curiel DT. Adenovirus-mediated delivery of p16 to p16-deficient human bladder cancer cells confers chemoresistance to cisplatin and paclitaxel. Clin Cancer Res 1997;3:2415–2423.

    PubMed  CAS  Google Scholar 

  286. 286. Sandig V, Brand K, Herwig S, Lukas J, Bartek J, Strauss M. Adenovirally transferred p16-INK4/CDKN2 and p53 genes cooperate to induce apoptotic tumour cell death. Nat Med 1997;3:313–319.

    Article  PubMed  CAS  Google Scholar 

  287. 287. Bonfanti M, Taverna S, Salmona M, D'Incalci M, Broggini M. p21WAF1-derived peptides linked to an internalization peptide inhibit human cancer cell growth. Cancer Res 1997;57:1442–1446.

    PubMed  CAS  Google Scholar 

  288. 288. Kato D, Miyazawa K, Ruas M, et al. Features of replicative senescence induced by direct addition of antennapedia-p16INK4A fusion protein to human diploid fibroblasts. FEBS Lett 1998;427:203–208.

    Article  PubMed  CAS  Google Scholar 

  289. 289. Fujimoto K, Hosotani R, Miyamoto Y, et al. Inhibition of pRb phosphorylation and cell cycle progression by an antennapedia-p16(INK4A) fusion peptide in pancreatic cancer cells. Cancer Lett 2000;159:151–158.

    Article  PubMed  CAS  Google Scholar 

  290. 290. Mutoh M, Lung FD, Long YQ, Roller PP, Sikorski RS, O'Connor PM. A p21(Waf1/Cip1)carboxyl-terminal peptide exhibited cyclin-dependent kinase-inhibitory activity and cytotoxicity when introduced into human cells. Cancer Res 1999;59:3480–3488.

    PubMed  CAS  Google Scholar 

  291. 291. Nagahara H, Vocero-Akbani AM, Snyder EL, et al. Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration. Nat Med 1998;4:1449–1452.

    Article  PubMed  CAS  Google Scholar 

  292. 292. Gius DR, Ezhevsky SA, Becker-Hapak M, Nagahara H, Wei MC, Dowdy SF. Transduced p16INK4a peptides inhibit hypophosphorylation of the retinoblastoma protein and cell cycle progression prior to activation of Cdk2 complexes in late G1. Cancer Res 1999;59:2577–2580.

    PubMed  CAS  Google Scholar 

  293. 293. Dai X, Yamasaki K, Yang L, et al. Keratinocyte G2/M growth arrest by 1,25-dihydroxyvitamin D3 is caused by Cdc2 phosphorylation through Wee1 and Myt1 regulation. J Invest Dermatol 2004;122:1356–1364.

    Article  PubMed  CAS  Google Scholar 

  294. 294. Leach SD, Scatena CD, Keefer CJ, et al. Negative regulation of Wee1 expression and Cdc2 phosphorylation during p53-mediated growth arrest and apoptosis. Cancer Res 1998;58:3231–3236.

    PubMed  CAS  Google Scholar 

  295. 295. Heald R, McLoughlin M, McKeon F. Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated Cdc2 kinase. Cell 1993;74:463–474.

    Article  PubMed  CAS  Google Scholar 

  296. 296. Wang Y, Li J, Booher RN, et al. Radiosensitization of p53 mutant cells by PD0166285, a novel G(2) checkpoint abrogator. Cancer Res 2001;61:8211–8217.

    PubMed  CAS  Google Scholar 

  297. 297. Donzelli M, Draetta GF. Regulating mammalian checkpoints through Cdc25 inactivation. EMBO Rep 2003;4:671–677.

    Article  PubMed  CAS  Google Scholar 

  298. 298. Kristjansdottir K, Rudolph J. Cdc25 phosphatases and cancer. Chem Biol 2004;11:1043–1051.

    Article  PubMed  CAS  Google Scholar 

  299. 299. Stegmeier F, Amon A. Closing mitosis: the functions of the Cdc14 phosphatase and its regulation. Annu Rev Genet 2004;38:203–232.

    Article  PubMed  CAS  Google Scholar 

  300. 300. Mailand N, Lukas C, Kaiser BK, Jackson PK, Bartek J, Lukas J. Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation. Nat Cell Biol 2002;4:317–322.

    Article  PubMed  CAS  Google Scholar 

  301. 301. Schwartz GK, Ilson D, Saltz L, et al. Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. J Clin Oncol 2001;19: 1985–1992.

    PubMed  CAS  Google Scholar 

  302. 302. Malumbres M. Therapeutic opportunities to control tumor cell cycles. Clin Transl Oncol 2006;8:399–408.

    Article  PubMed  CAS  Google Scholar 

  303. 303. Du J, Widlund HR, Horstmann MA, et al. Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Cancer Cell 2004;6:565–576.

    Article  PubMed  CAS  Google Scholar 

  304. 304. Emanuel S, Rugg CA, Gruninger RH, et al. The in vitro and in vivo effects of JNJ-7706621: a dual inhibitor of cyclin-dependent kinases and aurora kinases. Cancer Res 2005;65:9038–9046.

    Article  PubMed  CAS  Google Scholar 

  305. 305. Honda R, Lowe ED, Dubinina E, et al. The structure of cyclin E1/CDK2: implications for CDK2 activation and CDK2- independent roles. Embo J 2005;24:452–463.

    Article  PubMed  CAS  Google Scholar 

  306. 306. Mettus RV, Rane SG. Characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice. Oncogene 2003;22:8413–8421.

    Article  PubMed  CAS  Google Scholar 

  307. 307. Moons DS, Jirawatnotai S, Parlow AF, Gibori G, Kineman RD, Kiyokawa H. Pituitary hypoplasia and lactotroph dysfunction in mice deficient for cyclin-dependent kinase-4. Endocrinology 2002;143:3001–3008.

    Article  PubMed  CAS  Google Scholar 

  308. 308. Jirawatnotai S, Aziyu A, Osmundson EC, et al. Cdk4 is indispensable for postnatal proliferation of the anterior pituitary. J Biol Chem 2004;279:51100–51106.

    Article  PubMed  CAS  Google Scholar 

  309. 309. Moons DS, Jirawatnotai S, Tsutsui T, et al. Intact follicular maturation and defective luteal function in mice deficient for cyclin- dependent kinase-4. Endocrinol 2002;143:647–654.

    Article  CAS  Google Scholar 

  310. 310. Berthet C, Klarmann KD, Hilton MB, et al. Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation. Dev Cell 2006;10:563–573.

    Article  PubMed  CAS  Google Scholar 

  311. 311. Sicinski P, Donaher JL, Parker SB, et al. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 1995;82:621–630.

    Article  PubMed  CAS  Google Scholar 

  312. 312. Fantl V, Stamp G, Andrews A, Rosewell I, Dickson C. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev 1995;9:2364–2372.

    Article  PubMed  CAS  Google Scholar 

  313. 313. Deng C, Zhang P, Harper JW, Elledge SJ, Leder P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 1995;82:675–684.

    Article  PubMed  CAS  Google Scholar 

  314. 314. Geng Y, Whoriskey W, Park MY, et al. Rescue of cyclin D1 deficiency by knockin cyclin E. Cell 1999;97:767–777.

    Article  PubMed  CAS  Google Scholar 

  315. 315. Carthon BC, Neumann CA, Das M, et al. Genetic replacement of cyclin D1 function in mouse development by cyclin D2. Mol Cell Biol 2005;25:1081–1088.

    Article  PubMed  CAS  Google Scholar 

  316. 316. Sicinski P, Donaher JL, Geng Y, et al. Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 1996;384:470–474.

    Article  PubMed  CAS  Google Scholar 

  317. 317. Sicinska E, Aifantis I, Le Cam L, et al. Requirement for cyclin D3 in lymphocyte development and T cell leukemias. Cancer Cell 2003;4:451–461.

    Article  PubMed  CAS  Google Scholar 

  318. 318. Sicinska E, Lee YM, Gits J, et al. Essential role for cyclin D3 in granulocyte colony-stimulating factor-driven expansion of neutrophil granulocytes. Mol Cell Biol 2006;26:8052–8060.

    Article  PubMed  CAS  Google Scholar 

  319. 319. Cooper AB, Sawai CM, Sicinska E, et al. A unique function for cyclin D3 in early B cell development. Nat Immunol 2006;7:489–497.

    Article  PubMed  CAS  Google Scholar 

  320. 320. Kushner JA, Ciemerych MA, Sicinska E, et al. Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. Mol Cell Biol 2005;25:3752–3762.

    Article  PubMed  CAS  Google Scholar 

  321. 321. Bai F, Pei XH, Godfrey VL, Xiong Y. Haploinsufficiency of p18(INK4c) sensitizes mice to carcinogen-induced tumorigenesis. Mol Cell Biol 2003;23:1269–1277.

    Article  PubMed  CAS  Google Scholar 

  322. 322. Zindy F, van Deursen J, Grosveld G, Sherr CJ, Roussel MF. INK4d-deficient mice are fertile despite testicular atrophy. Mol Cell Biol 2000;20:372–378.

    Article  PubMed  CAS  Google Scholar 

  323. 323. Chen P, Zindy F, Abdala C, et al. Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d. Nat Cell Biol 2003;5:422–426.

    Article  PubMed  CAS  Google Scholar 

  324. 324. Zindy F, den Besten W, Chen B, et al. Control of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors p18(Ink4c) and p19(Ink4d). Mol Cell Biol 2001;21:3244–3255.

    Article  PubMed  CAS  Google Scholar 

  325. 325. Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ. The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature 1998;396:177–180.

    Article  PubMed  CAS  Google Scholar 

  326. 326. Jirawatnotai S, Moons DS, Stocco CO, et al. The cyclin-dependent kinase inhibitors p27Kip1 and p21Cip1 cooperate to restrict proliferative life span in differentiating ovarian cells. J Biol Chem 2003;278:17021–17027.

    Article  PubMed  CAS  Google Scholar 

  327. 327. Zhang P, Wong C, Liu D, Finegold M, Harper JW, Elledge SJ. p21(CIP1) and p57(KIP2) control muscle differentiation at the myogenin step. Genes Dev 1999;13:213–224.

    Article  PubMed  CAS  Google Scholar 

  328. 328. Zhang P, Wong C, DePinho RA, Harper JW, Elledge SJ. Cooperation between the Cdk inhibitors p27(KIP1) and p57(KIP2) in the control of tissue growth and development. Genes Dev 1998;12:3162–3167.

    Article  PubMed  CAS  Google Scholar 

  329. 329. Franklin DS, Godfrey VL, O'Brien DA, Deng C, Xiong Y. Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. Mol Cell Biol 2000;20:6147–6158.

    Article  PubMed  CAS  Google Scholar 

  330. 330. Zindy F, Cunningham JJ, Sherr CJ, Jogal S, Smeyne RJ, Roussel MF. Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases. Proc Natl Acad Sci USA 1999;96:13462–13467.

    Article  PubMed  CAS  Google Scholar 

  331. 331. Pei XH, Bai F, Tsutsui T, Kiyokawa H, Xiong Y. Genetic evidence for functional dependency of p18Ink4c on Cdk4. Mol Cell Biol 2004;24:6653–6664.

    Article  PubMed  CAS  Google Scholar 

  332. 332. Geng Y, Yu Q, Sicinska E, Das M, Bronson RT, Sicinski P. Deletion of the p27Kip1 gene restores normal development in cyclin D1-deficient mice. Proc Natl Acad Sci USA 2001;98:194–199.

    Article  PubMed  CAS  Google Scholar 

  333. 333. Tong W, Pollard JW. Genetic evidence for the interactions of cyclin D1 and p27(Kip1) in mice. Mol Cell Biol 2001;21:1319–1328.

    Article  PubMed  CAS  Google Scholar 

  334. 334. Hacker E, Muller HK, Irwin N, et al. Spontaneous and UV radiation-induced multiple metastatic melanomas in Cdk4R24C/R24C/TPras mice. Cancer Res 2006;66:2946–2952.

    Article  PubMed  CAS  Google Scholar 

  335. 335. Tormo D, Ferrer A, Gaffal E, et al. Rapid growth of invasive metastatic melanoma in carcinogen-treated hepatocyte growth factor/scatter factor-transgenic mice carrying an oncogenic CDK4 mutation. Am J Pathol 2006;169:665–672.

    Article  PubMed  CAS  Google Scholar 

  336. 336. Miliani de Marval PL, Macias E, Rounbehler R, et al. Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissues. Mol Cell Biol 2004;24:7538–7547.

    Article  PubMed  CAS  Google Scholar 

  337. 337. Fukuoka K, Usuda J, Iwamoto Y, et al. Mechanisms of action of the novel sulfonamide anticancer agent E7070 on cell cycle progression in human non-small cell lung cancer cells. Invest New Drugs 2001;19:219–227.

    Article  PubMed  CAS  Google Scholar 

  338. 338. Mesguiche V, Parsons RJ, Arris CE, et al. 4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2. Bioorganic Med Chem Lettrs 2003;13:217–222.

    Article  CAS  Google Scholar 

  339. 339. Payton M, Chung G, Yakowec P, et al. Discovery and evaluation of dual CDK1 and CDK2 inhibitors. Cancer Res 2006;66: 4299–4308.

    Article  PubMed  CAS  Google Scholar 

  340. 340. Pennati M, Campbell AJ, Curto M, et al. Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation. Mol Cancer Ther 2005;4:1328–1337.

    Article  PubMed  CAS  Google Scholar 

  341. 341. Vassilev LT, Tovar C, Chen S, et al. Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1. Proc Natl Acad Sci USA 2006;103:10660–10665.

    Article  PubMed  CAS  Google Scholar 

  342. 342. Brooks EE, Gray NS, Joly A, et al. CVT-313, a specific and potent inhibitor of CDK2 that prevents neointimal proliferation. J Biol Chem 1997;272:29207–29211.

    Article  PubMed  CAS  Google Scholar 

  343. 343. Ely S, Di Liberto M, Niesvizky R, et al. Mutually exclusive cyclin-dependent kinase 4/cyclin D1 and cyclin-dependent kinase 6/cyclin D2 pairing inactivates retinoblastoma protein and promotes cell cycle dysregulation in multiple myeloma. Cancer Res 2005;65:11345–11353.

    Article  PubMed  CAS  Google Scholar 

  344. 344. Rossi AG, Sawatzky DA, Walker A, et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med 2006;12:1056–1064.

    Article  PubMed  CAS  Google Scholar 

  345. 345. Broxterman HJ, Georgopapadakou NH. Anticancer therapeutics: “Addictive” targets, multi-targeted drugs, new drug combinations. Drug Resistance Updates 2005;8:183–197.

    Article  PubMed  CAS  Google Scholar 

  346. 346. Mahale S, Aubry C, James Wilson A, et al. CA224, a non-planar analogue of fascaplysin, inhibits Cdk4 but not Cdk2 and arrests cells at G0/G1 inhibiting pRB phosphorylation. Bioorganic Med Chem Lettrs 2006;16:4272–4278.

    Article  CAS  Google Scholar 

  347. 347. Wang Q, Fan S, Eastman A, Worland PJ, Sausville EA, O'Connor PM. UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J Natl Cancer Inst 1996;88:956–965.

    Article  PubMed  CAS  Google Scholar 

  348. 348. Jackson JR, Gilmartin A, Imburgia C, Winkler JD, Marshall LA, Roshak A. An indolocarbazole inhibitor of human checkpoint kinase (Chk1) abrogates cell cycle arrest caused by DNA damage. Cancer Res 2000;60:566–572.

    PubMed  CAS  Google Scholar 

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Acknowledgments

I thank J Lahti for advice on CDK11 and cyclin L genes and M Barbacid for helpful discussions. Work in my laboratory is funded by grants from the Fundación de la Asociación Española contra el Cáncer (AECC), Fundación Médica de la Mutua Madrileña Automovilística, Comunidad de Madrid, and Ministry of Education and Science (BMC2003-06098).

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Malumbres, M. (2008). Cyclin-Dependent Kinases and Their Regulators as Potential Targets for Anticancer Therapeutics. In: Bronchud, M.H., Foote, M.A., Giaccone, G., Olopade, O., Workman, P. (eds) Principles of Molecular Oncology. Humana Press. https://doi.org/10.1007/978-1-59745-470-4_10

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