Skip to main content
SpringerLink
Log in

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

  • Chapter
Principles of Molecular Oncology

Abstract

A number of complex changes take place between the time a cell is formed and the time it divides into two daughter cells. This process is known as the cell cycle. The morphologic changes associated with particular stages of the cell cycle are well known; however, a detailed understanding of the regulatory mechanisms controlling cell-cycle progression has only recently been elucidated. Understanding the biochemical and genetic mechanisms that control these cellular changes is fundamental to cell biology because it influences processes such as cell transformation, cell differentiation, and cell growth. A greater knowledge of the molecular mechanisms underlying the transformation of mammalian cells may allow the design of inhibitors of the specific biochemical processes responsible for abnormal cell proliferation or cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 74.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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 

  2. Masui Y, Markert CL. Cytoplasmic control of nuclear behavior during meiotic maturation of frog oocytes. J Exp Zool. 1971; 177: 129–145.

    Article  PubMed  CAS  Google Scholar 

  3. Hartwell LH, et al. Checkpoints-controls that ensure the order of cell-cycle events. Science. 1989; 246: 629–634.

    Article  PubMed  CAS  Google Scholar 

  4. Gould KL, Nurse P. Tyrosine phosphorylation of the fission yeast cdc2+ protein-kinase regulates entry into mitosis. Nature. 1989; 342: 39–45.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  6. Masui Y, Markert C. Cytoplasmic control of nuclear behaviour during meiotic maturation of frog oocytes. J Exp Zool. 1971; 177: 129–134.

    Article  PubMed  CAS  Google Scholar 

  7. Smith LD, Ecker RE. Interaction of steroids with Rana pipiens oocytes in the induction of maturation. Dev Biol. 1971; 25: 232–237.

    Article  PubMed  CAS  Google Scholar 

  8. Enquist BJ, et al. Allometric scaling of plant energetics and population density. Nature. 1998; 395: 163–165.

    Article  CAS  Google Scholar 

  9. West GB, Browa JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science. 1997; 276: 122–126.

    Article  PubMed  CAS  Google Scholar 

  10. Kretzschmar M, Massague J. SMADs: mediators and regulators of TGF-beta signaling. Curr Opin Genet Dev. 1998; 8: 103–111.

    Article  PubMed  CAS  Google Scholar 

  11. Lo RS, Chen YG, Shi Y, et al. The L3 loop: a structural motif determining specific interactions between SMAD proteins and TGF-beta receptors. EMBO J. 1998; 17: 996–1005.

    Article  PubMed  CAS  Google Scholar 

  12. Hata A, Lagna G, Massague J, Hemmati-Brivanlou A. Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev. 1998; 12: 186–197.

    Article  PubMed  CAS  Google Scholar 

  13. Shi Y, Hata A, Lo RS, et al. A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature. 1997; 388: 87–93.

    Article  PubMed  CAS  Google Scholar 

  14. Hainaut P. The tumor suppressor protein p53: a receptor to genotoxic stress that controls cell growth and survival. Curr OpinOncol. 1995; 7: 76–82.

    CAS  Google Scholar 

  15. Bates S, Vousden KH. p 53 in signaling checkpoint arrest or apoptosis. Curr Opin Genet Dev. 1996; 6: 12–19.

    Article  PubMed  CAS  Google Scholar 

  16. Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med. 2002; 347: 1593–1603.

    Article  PubMed  CAS  Google Scholar 

  17. Sherr CJ. The ink4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol. 2001; 2: 731–737.

    Article  PubMed  CAS  Google Scholar 

  18. Pardee AB. G1 events and regulation of cell proliferation. Science. 1989; 246: 603–608.

    Article  PubMed  CAS  Google Scholar 

  19. Morgan DO. Principles of CDK regulation. Nature. 1995; 374: 131–135.

    Article  PubMed  CAS  Google Scholar 

  20. Hunter T, Pines J. Cyclins and cancer. II. Cyclin D and CDK inhibitors come of age. Cell. 1994; 79: 573–582.

    Article  PubMed  CAS  Google Scholar 

  21. Marin O, Meggio F, Draetta G, Pinna LA. The consensus sequences for cdc2 kinase and for casein kinase-2 are mutually incompatible. A study with peptides derived from the ß-subunit of casein kinase-w. FEBS Lett. 1992; 301: 111–114.

    Article  PubMed  CAS  Google Scholar 

  22. Songyang Z, Blechner S, Hoagland N, Hoekstra MF, Piwnica-Worms H, Cantley LC. Use of an oriented peptide library to determine the optimal substrates of protein kinases. Curr Biol. 1994; 4: 973–982.

    Article  PubMed  CAS  Google Scholar 

  23. Connell-Crowley L, Harper JW, Goodrich DW. Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation. Mol Biol Cell. 1997; 8: 287–301.

    PubMed  CAS  Google Scholar 

  24. Xiong Y, Zhang H, Beach D. Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Genes Dev. 1993; 7: 1572–1583.

    Article  PubMed  CAS  Google Scholar 

  25. Tsai LH, Delalle I, Caviness VS Jr, Chae T, Harlow E. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature. 1994; 371: 419–423.

    CAS  Google Scholar 

  26. Jones KA. Taking a new TAK on tat transactivation. Genes Dev. 1997; 11: 2593–2599.

    Article  PubMed  CAS  Google Scholar 

  27. Lees EM, Harlow E. Sequences within the conserved cyclin box of human cyclin A are sufficient for binding to and activation of cdc2 kinase. Mol Cell Biol. 1993; 13: 1194–1201.

    PubMed  CAS  Google Scholar 

  28. 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 

  29. 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 

  30. 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 

  31. Kato JY, Matsuoka M, Polyak K, Massague J, Sherr CJ. Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (P27Kip1) of cyclin-dependent kinase 4 activation. Cell. 1994; 79: 487–496.

    Article  PubMed  CAS  Google Scholar 

  32. Massague J, Polyak K. Mammalian antiproliferative signals and their targets. Curr Opin Genet Dev. 1995; 5: 91–96.

    Article  PubMed  CAS  Google Scholar 

  33. Dulic V, Kaufmann WK, Wilson SJ, et al. p53–dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell. 1994; 76: 1013–1023.

    Article  PubMed  CAS  Google Scholar 

  34. El-Deiry WS, Tokino T, Waldman T, et al. Topological control of p21WAF1/CIP1 expression in normal and neoplastic tissues. Cancer Res. 1995; 55: 2910–2919.

    PubMed  CAS  Google Scholar 

  35. Rudner AD, Murray AW. The spindle assembly checkpoint. Curr Opin Cell Biol. 1996; 8: 773–780.

    Article  PubMed  CAS  Google Scholar 

  36. O’Connor PM. In: Checkpoint Controls and Cancer (Kastan MB, ed.), Imperial Cancer Research Fund, Cold Spring Harbor Press, Plainview, NY, 1997; pp. 151–182.

    Google Scholar 

  37. Jin DY, Spencer F, Jeang KT. Human T cell leukemia virus type 1 oncoprotein tax targets the human mitotic checkpoint protein MAD1. Cell. 1998; 93: 81–91.

    Article  PubMed  CAS  Google Scholar 

  38. Draetta GF. Mammalian G-1 cyclins. Curr Opin Cell Biol. 1994; 6: 842–846.

    Article  PubMed  CAS  Google Scholar 

  39. Terada Y, Tatsuka M, Jinno S, Okayama H. Requirement for tyrosine phosphorylation of Cdk4 in G1 arrest induced by ultraviolet irradiation. Nature. 1995; 376: 357–362.

    Article  Google Scholar 

  40. Ohtsubo M, Roberts JM. Cyclin-dependent regulation of G1 in mammalian fibroblasts. Science. 1993; 259: 1907–1912.

    Article  Google Scholar 

  41. Lukas J, Herzinger T, Hansen K, et al. Cyclin E-induced S phase without activation of the pRb/E2F pathway. Genes Dev. 1997; 11: 1479–1492.

    Article  PubMed  CAS  Google Scholar 

  42. Alevizopoulos K, Vlach J, Hennecke S, Amati B. Cyclin E and c-Myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins. EMBO J. 1997; 16: 5322–5333.

    CAS  Google Scholar 

  43. Papano M, Pepperkok R, Verde F, Ansorge W, Draetta GF. Cyclin A is required at two points in the human cell cycle. EMBO J. 1992; 11: 961–971.

    Google Scholar 

  44. Dunphy WG, Brizuela L, Beach D, Newport J. The Xenopus cdc2 protein is a component of MPF, a cytoplasmic regulator of mitosis. Cell. 1988; 54: 423–431.

    Article  PubMed  CAS  Google Scholar 

  45. 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 

  46. Arion D, Meijer L, Brizuela L, Beach D. cdc2 is a component of the M phase-specific histone H1 kinase: evidence for identity with MPF. Cell. 1988; 55: 371–378.

    Article  PubMed  CAS  Google Scholar 

  47. Rao PN, Johnson RT. Mammalian cell fusion: studies on the regulation of DNA synthesis and mitosis. Nature. 1970; 225: 159–164.

    Article  PubMed  CAS  Google Scholar 

  48. Murray AW, Solomon MJ, Kirschner MW. The role of cyclin synthesis and degradation in the control of maturation promoting factor activity. Nature. 1989; 339: 280–286.

    Article  PubMed  CAS  Google Scholar 

  49. Peters JM, King RW, Hoeoeg C, Kirschner MW. Identification of BIME as a subunit of the anaphase-promoting complex. Science. 1996; 274: 1199–1201.

    Article  PubMed  CAS  Google Scholar 

  50. Basi G, Draetta G. The cdk2 kinase: structure, activation, and its role at mitosis in vertebrate cells. In: Cell Cycle Control. ( Hutchinson C, Glover DM, eds.), IRL Press, Oxford, UK, 1995; pp. 107–143.

    Google Scholar 

  51. 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  Google Scholar 

  52. 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 

  53. 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 

  54. Pines J. Cell cycle: confirmation change. Nature. 1995; 376: 294–295.

    Article  PubMed  CAS  Google Scholar 

  55. 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 

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

    Article  PubMed  CAS  Google Scholar 

  57. Serizawa H, Maekelae TP, Conaway JW, Conaway RC, Weinberg RA, Young RA. Association of Cdk-activating kinase subunits with transcription factor TFIIH. Nature. 1995; 374: 280–282.

    Article  PubMed  CAS  Google Scholar 

  58. Espinoza FH, Farrell A, Erdjument-Bromage H, Tempst P, Morgan DO. A cyclin-dependent kinase-activating kinase (CAK) in budding yeast unrelated to vertebrate CAK. Science. 1996; 273: 1714–1717.

    Article  PubMed  CAS  Google Scholar 

  59. Lew DJ, Kornbluth S. Regulatory roles of cyclin dependent kinase phosphorylation in cell cycle control. Curr Opin Cell Biol. 1996; 8: 795–804.

    Article  PubMed  CAS  Google Scholar 

  60. Coleman TR, Dunphy WG. Cdc2 regulatory factors. Curr Opin Cell Biol. 1994; 6: 877–882.

    Article  PubMed  CAS  Google Scholar 

  61. Mueller PR, Coleman TR, Kumagai A, Dunphy WG. Myt1: a membrane-associated inhibitory kinase that phosphorylates Cdc2 on both threonine-14 and tyrosine-15. Science. 1995; 270: 86–90.

    Article  PubMed  CAS  Google Scholar 

  62. Parker LL, Piwnica-Worms H. Inactivation of the p34cdc2–cyclin B complex by the human WEE1 tyrosine kinase. Science. 1992; 257: 1955–1957.

    Article  PubMed  CAS  Google Scholar 

  63. Galaktionov K, Lee AK, Eckstein J, et al. CDC25 phosphatases as potential human oncogenes. Science. 1995; 269: 1575–1577.

    Article  PubMed  CAS  Google Scholar 

  64. Hoffmann I, Clarke PR, Marcote MJ, Karsenti E, Draetta GF. Phosphorylation and activation of human cdc25–C by cdc2–cyclin B and its involvement in the self-amplification of MPF at mitosis. EMBO J. 1993; 12: 53–63.

    PubMed  CAS  Google Scholar 

  65. Kumagai A, Dunphy WG. Regulation of the cdc25 protein during the cell cycle in Xenopus extracts. Cell. 1992; 70: 139–151.

    Article  PubMed  CAS  Google Scholar 

  66. Kumagai A, Yakowec PS, Dunphy WG. 14–3–3 Proteins act as negative regulators of the mitotic inducer Cdc25 in Xenopus egg extracts. Mol Biol Cell. 1998; 9: 345–354.

    PubMed  CAS  Google Scholar 

  67. Lopez-Girona A, Furnari B, Mondesert O, Russel P. Nuclear localization of Cdc25 is regulated by DNA damage and a 14–3–3 protein. Nature. 1999; 397: 172–175.

    Article  PubMed  CAS  Google Scholar 

  68. Matsuoka S, Huang M, Elledge SJ. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science. 1998; 282: 1893–1897.

    Article  PubMed  CAS  Google Scholar 

  69. Sanchez Y, Wong C, Thoma RS, et al. Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage of Cdk regulation through Cdc25. Science. 1997; 277: 1497–1501.

    Article  PubMed  CAS  Google Scholar 

  70. Peng CY, Graves PR, Ogg S, et al. C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14–3–3 protein binding. Cell Growth Differ. 1998; 9: 197–208.

    PubMed  CAS  Google Scholar 

  71. Harper JW. In: Checkpoint Controls and Cancer. (Kastan MB, ed.), ICRF, Cold Spring Harbor Press, Plainview, NY, 1997; pp. 91–107.

    Google Scholar 

  72. 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 

  73. 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 

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

    Article  PubMed  CAS  Google Scholar 

  75. 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 

  76. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci USA. 1998; 95: 8292–8297.

    Article  PubMed  CAS  Google Scholar 

  77. Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA. Role of the INK4a locus in tumor suppression and cell mortality. Cell. 1996; 85: 27–37.

    Article  PubMed  CAS  Google Scholar 

  78. Kamijo T, Zindy F, Roussel MF, et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell. 1997; 91: 649–659.

    Article  PubMed  CAS  Google Scholar 

  79. Halevy O, Novitch BG, Spicer DB, et al. Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science. 1995; 267: 1017–1021.

    Article  Google Scholar 

  80. Polyak K, Kato J, Solomon C, et al. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-ß and contact inhibition to cell cycle arrest. Genes Dev. 1994; 8: 9–22.

    Article  PubMed  CAS  Google Scholar 

  81. 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 

  82. Vlach J, Hennecke S, Amati B. Phosphorylation-dependent degradation of the cyclindependent kinase inhibitor p27. EMBO J. 1997; 16: 5334–5344.

    Article  PubMed  CAS  Google Scholar 

  83. 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 couples. Nature. 1996; 382: 325–331.

    Article  PubMed  CAS  Google Scholar 

  84. Adams PD, Sellers WR, Sharma SK, Wu AD, Nalin CM, Kaelin WG. Identification of a cyclin–cdk2 recognition motif present in substrates and p21–like cyclin-dependent kinase inhibitors. Mol Cell Biol. 1996; 16: 6623–6633.

    PubMed  CAS  Google Scholar 

  85. Chen J, Saha P, Kornbluth S, Dynlacht BD, Dutta A. Cyclin-binding motifs are essential for the function of p21CIP1. Mol Cell Biol. 1996; 16: 4673–4682.

    PubMed  CAS  Google Scholar 

  86. Reynisdottir I, Massague J. The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dev. 1997; 11: 492–503.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  88. 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.

    CAS  Google Scholar 

  89. 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 

  90. 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 

  91. Cheng M, Sexl V, Sherr CJ, Roussel MF. Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1). Proc Natl Acad Sci USA. 1998; 95: 1091–1096.

    Article  PubMed  CAS  Google Scholar 

  92. Lamphere L, Fiore F, Xu X, et al. Interaction between Cdc37 and Cdk4 in human cells. Oncogene. 1997; 14: 1999–2004.

    Article  PubMed  CAS  Google Scholar 

  93. Gyuris J, Golemis E, Chertkov H, Brent R. Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2. Cell. 1993; 75: 791–803.

    Article  PubMed  CAS  Google Scholar 

  94. Hartwell LH, Kastan MB. Cell cycle control and cancer. Science. 1994; 266: 1821–1828.

    Article  PubMed  CAS  Google Scholar 

  95. Lammie GA, Peters G. Chromosome 11q13 abnormalities in human cancer. Cancer Cells. 1991; 3: 413–420.

    PubMed  CAS  Google Scholar 

  96. Rabbitts TH. Chromosomal translocations in human cancer. Nature. 1994; 372: 143–149.

    Article  PubMed  CAS  Google Scholar 

  97. Shivdasani RA, Hess JL, Skarin AT, Pinkus GS. Intermediate lymphocytic lymphoma: clinical and pathologic features of a recently characterized subtype of non-Hodgkin’s lymphoma. J Clin Oncol. 1993; 11: 802–811.

    PubMed  CAS  Google Scholar 

  98. 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 

  99. 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: 9637–9642.

    Google Scholar 

  100. Bosch F, Jares P, Campo E, et al. PRAD-1/cyclin D1 gene overexpression in chronic lymphoproliferative disorder: a highly specific marker of mantle cell lymphoma. Blood. 1994; 84: 2726–2732.

    PubMed  CAS  Google Scholar 

  101. de Boer CJ, van Krieken JH, Kluin-Nelemans HC, Kluin PM, Schuuring E. Cyclin D1 messenger RNA overexpression as a marker for mantle cell lymphoma. Oncogene. 1995; 10: 1833–1840.

    PubMed  Google Scholar 

  102. Arnold A, Kim HG, Gaz RD, et al. Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest. 1989; 83: 2034–2040.

    Article  PubMed  CAS  Google Scholar 

  103. 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 

  104. Lammie GA, Fantl V, Smith R, et al. D1 1S287, a putative oncogene on chromosome 1 1q13, is amplified and expressed in squamous cell and mammary carcinomas and linked to BCL-1. Oncogene. 1991; 6: 439–444.

    PubMed  CAS  Google Scholar 

  105. Buckley MF, Sweeney KJ, Hamilton JA, et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene. 1993; 8: 2127–2133.

    PubMed  CAS  Google Scholar 

  106. Fantl V, Smith R, Brookes S, Dickson C, Peters G. Chromosomes 11q13 abnormalities in human breast cancer. Cancer Surv. 1993; 18: 77–94.

    PubMed  CAS  Google Scholar 

  107. Gaffey MJ, Frierson HF Jr, Williams ME. Chromosome 1 1q13, c-erB-2, and c-myc amplification in invasive breast carcinoma: clinicopathologic correlations. Mod Pathol. 1993; 6: 654–659.

    PubMed  CAS  Google Scholar 

  108. Parise O Jr, Janot F, Guerry R, et al. Chromosome 1 1q13 gene amplifications in head and neck squamous cell carcinomas: relation with lymph node invasion. Int J Oncol. 1994; 5: 309–313.

    PubMed  CAS  Google Scholar 

  109. Pacilio C, Germano D, Addeo R, et al. Constitutive overexpression of cyclin D1 does not prevent inhibition of hormone-responsive human breast cancer cell growth by antiestrogens. Cancer Res. 1998; 58: 871–876.

    PubMed  CAS  Google Scholar 

  110. 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 

  111. 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 

  112. Champerne MH, Bieche I, Lizard S, Lidereau R. 1 1q13 amplification in local recurrence of human primary breast cancer. Genes Chromo Cancer. 1995; 12: 127–133.

    Google Scholar 

  113. Zhang SY, Caamano J, Cooper F, Guo X, Klein-Szanto AJ. Immunohistochemistry of cyclin D1 in human breast cancer. Am J Clin Pathol. 1994; 102: 695–698.

    PubMed  CAS  Google Scholar 

  114. Rubin JS, Qiu L, Etkind P. Amplification of the Int-2 gene in head and neck squamous cell carcinoma. J Laryngol Otol. 1995; 109: 72–76.

    PubMed  CAS  Google Scholar 

  115. Xu L, Davidson BJ, Murty VV, et al. TP53 gene mutations and CCND1 gene amplification in head and neck squamous cell carcinoma cell line. Int J Cancer. 1994; 59: 383–387.

    Article  PubMed  CAS  Google Scholar 

  116. Adelaide J, Monges G, Derderian C, Seitz JF, Birnbaum D. Oesophageal cancer and amplification of the human cyclin D gene CCND1/PRAD1. Br J Cancer. 1995; 71: 64–68.

    Article  PubMed  CAS  Google Scholar 

  117. Yoshida K, Kawami H, Kuniyasu H, et al. Coamplification of cyclin D, hst-1 and int-2 genes is a good biological marker of high malignancy for human esophageal carcinomas. Oncol Rep. 1994; 1: 493–496.

    PubMed  CAS  Google Scholar 

  118. Marchetti A, Doglioni C, Barbareschi M, et al. Cyclin D1 and retinoblastoma susceptibility gene alterations in non-small cell lung cancer. Int J Cancer. 1998; 75: 187–192.

    Article  PubMed  CAS  Google Scholar 

  119. Gansauge S, Gansauge F, Ramadani M, et al. Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res. 1997; 57: 1634–1637.

    PubMed  CAS  Google Scholar 

  120. Huang L, Lang D, Geradts J, et al. Molecular and immunochemical analyses of RB 1 and cyclin D1 in human duct pancreatic carcinomas and cell lines. Mol Carcinog. 1996; 15: 85–95.

    Article  PubMed  CAS  Google Scholar 

  121. Demetrick DJ, Zhang H, Beach DH. Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes. Cytogenet Cell Genet. 1994; 66: 72–74.

    Article  PubMed  CAS  Google Scholar 

  122. Mandahl N, Heim S, Johansson B, et al. Lipomas have characteristic structural chromosomal rearrangements of 12q13–q14. Int J Cancer. 1987; 39: 685–688.

    Article  PubMed  CAS  Google Scholar 

  123. Turc-Carel C, Limon J, Dal Cin P, Rao U, Karakousis C, Sandberg AA. Cytogenetic studies of adipose tissue tumors. II. Recurrent reciprocal translocation t(12;16)(q13;p11) in myxoid liposarcomas. Cancer Genet Cytogenet. 1986; 23: 291–299.

    Article  PubMed  CAS  Google Scholar 

  124. Fischer U, Meltzer P, Meese E. Twelve amplified and expressed genes localized in a single domain in glioma. Hum Genet. 1996; 98: 625–628.

    Article  PubMed  CAS  Google Scholar 

  125. Berner JM, Forus A, Elkahloun A, Meltzer PS, Fodstad O, Myklebost O. Separate amplified regions encompassing CDK4 and MDM2 in human sarcomas. Genes Chromos Cancer. 1996; 17: 254–259.

    Article  PubMed  CAS  Google Scholar 

  126. Ladanyi M, Lewis R, Jhanwar SC, Gerald W, Huvos AG, Healey JH. MDM2 and CDK4 gene amplification in Ewing’s sarcoma. J Pathol. 1995; 175: 211–217.

    Article  PubMed  CAS  Google Scholar 

  127. Reifenberger G, Reifenberger J, Ichimura K, Meltzer PS, Colllins VP. Amplification of multiple genes from chromosomal region 12q13–14 in human malignant gliomas: preliminary mapping of the amplicons shows preferential involvement of CDK4, SAS, and MDM2. Cancer Res. 1994; 54: 4299–4303.

    PubMed  CAS  Google Scholar 

  128. Maelandsmo GM, Berner JM, Florenes VA, et al. Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas-relationship to amplification and mRNA levels of CDK4 and CCND1. Br J Cancer. 1995; 72: 393–398.

    Article  PubMed  CAS  Google Scholar 

  129. Kovar H, Jug G, Aryee DN, et al. Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors. Oncogene. 1997; 15: 2225–2232.

    Article  PubMed  CAS  Google Scholar 

  130. 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 

  131. He J, Olson JJ, James CD. Lack of p16INK4 or retinoblastoma protein (pRb), or amplification-associated overexpression of cdk4 is observed in distinct subsets of malignant glial tumors and cell lines. Cancer Res. 1995; 55: 4833–4836.

    PubMed  CAS  Google Scholar 

  132. Petronio J, He J, Fults D, Pedone C, James CD, Allen JR. Common alternative gene alterations in adult malignant astrocytomas, but not in childhood primitive neuroectodermal tumors: P16ink4 homozygous deletions and CDK4 gene amplifications. J Neurosurg. 1996; 84: 1020–1023.

    Article  PubMed  CAS  Google Scholar 

  133. 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 

  134. Cordon-Cardo C, Latres E, Drobnjak M, et al. Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer Res. 1994; 54: 794–799.

    PubMed  CAS  Google Scholar 

  135. He J, Allen JR, Collins PV, 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 

  136. 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 

  137. Woelfel 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  CAS  Google Scholar 

  138. Zuo L, Weger J, Wang 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 

  139. 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 

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

    Article  PubMed  CAS  Google Scholar 

  141. Einhorn S, Heyman M. Chromosome 9 short arm deletions in malignant diseases. Leuk Lymphoma. 1993; 11: 191–196.

    Article  PubMed  CAS  Google Scholar 

  142. Cannon-Albright LA, Goldgar DE, Meyer LJ, et al. Assignment of a locus for familial melanoma, MLM, to chromosome 9p13–p22. Science. 1992; 258: 1147–1152.

    Article  Google Scholar 

  143. 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 

  144. Pomerantz J, Schreiber-Agus N, Liegeois NJ, et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53. Cell. 1998; 92: 713–723.

    Article  PubMed  CAS  Google Scholar 

  145. Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell. 1998; 92: 725–734.

    Article  PubMed  CAS  Google Scholar 

  146. 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 

  147. Palmero I, Peters G. Perturbation of cell cycle regulators in human cancer. Cancer Surv. 1996; 27: 351–367.

    PubMed  CAS  Google Scholar 

  148. Foulkes WD, Flanders TY, Pollock PM, Hayward NK. The CDKN2A (p16) gene and human cancer. Mol Med. 1997; 3: 5–20.

    PubMed  CAS  Google Scholar 

  149. Merlo A, Herman JG, Mao L, et al. 5 CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995; 1: 686–692.

    Article  PubMed  CAS  Google Scholar 

  150. Herman JG, Merlo A, Mao L, et al. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 1995; 55: 4525–4530.

    PubMed  CAS  Google Scholar 

  151. Quelle DE, Cheng M, Ashmun RA, Sherr CJ. Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p 16INK4a but not by the alternative reading frame protein p 19ARF. Proc Natl Acad Sci USA. 1997; 94: 669–673.

    Article  PubMed  CAS  Google Scholar 

  152. Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv Cancer Res. 1996; 68: 67–108.

    Article  PubMed  CAS  Google Scholar 

  153. Shapiro GI, Edwards CD, Kobzik L, et al. Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines. Cancer Res. 1995; 55: 505–509.

    PubMed  CAS  Google Scholar 

  154. Pietenpol JA, Bohlander SK, Sato Y, et al. Assignment of the human p27Kip1 gene to 12p13 and its analysis in leukemias. Cancer Res. 1995; 55: 1206–1210.

    PubMed  CAS  Google Scholar 

  155. Ponce-Castaneda MV, Lee MH, Latres E, et al. p27Kip1: chromosomal mapping to 12p12– 12p13.1 and absence of mutations in human tumors. Cancer Res. 1995; 55: 1211–1214.

    PubMed  CAS  Google Scholar 

  156. 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 

  157. 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: 227–231.

    Article  PubMed  CAS  Google Scholar 

  158. 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 

  159. Mori M, Mimori K, Shiraishi T, et al. p27 expression and gastric carcinoma (letter). Nat Med. 1997; 3: 593.

    Article  PubMed  CAS  Google Scholar 

  160. Tan P, Cady B, Wanner M, et al. The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a,b) invasive breast carcinomas. Cancer Res. 1997; 57: 1259–1263.

    PubMed  CAS  Google Scholar 

  161. Yang RM, Naitoh J, Murphy M, et al. Low p27 expression predicts poor disease-free survival in patients with prostate cancer. J Urol. 1998; 159: 941–945.

    Article  PubMed  CAS  Google Scholar 

  162. Tsihlias J, Kapusta LR, DeBoer G, et al. Loss of cyclin-dependent kinase inhibitor p27Kip1 is a novel prognostic factor in localized human prostate adenocarcinoma. Cancer Res. 1998; 58: 542–548.

    PubMed  CAS  Google Scholar 

  163. Singh SP, Lipman J, Goldman H, et al. Loss or altered subcellular localization of p27 in Barrett’s associated adenocarcinoma. Cancer Res. 1998; 58: 1730–1735.

    PubMed  CAS  Google Scholar 

  164. St. Croix B, Florenes VA, Rak JW, et al. Impact of the cyclin-dependent kinase inhibitor p27Kip 1 on resistance of tumour cells to anticancer agents. Nat Med. 1996; 2: 1204–1210.

    Google Scholar 

  165. Zhu X, Ohtsubo M, Boehmer RM, Roberts JM, Assoian RK. Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclin E-cdk2, and phosphorylation of the retinoblastoma protein. J Cell Biol. 1996; 133: 391–403.

    Article  PubMed  CAS  Google Scholar 

  166. Ciaparrone M, Yamamoto H, Yao Y, et al. Localization and expression of p27KIP1 in multistage colorectal carcinogenesis. Cancer Res. 1998; 58: 114–122.

    PubMed  CAS  Google Scholar 

  167. Keyomarsi K, O’Leary N, Molnar G, Lees E, Fingert HJ, Pardee AB. Cyclin E, a potential prognostic marker for breast cancer. Cancer Res. 1994; 54: 380–385.

    PubMed  CAS  Google Scholar 

  168. 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 

  169. 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 

  170. Wang J, Chenivesse X, Henglein B, Brechot C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature. 1990; 343: 555–557.

    Article  PubMed  CAS  Google Scholar 

  171. Wang J, Zindy F, Chenivesse X, Lamas E, Henglein B, Brechot C. Modification of cyclin A expression by hepatitis B virus DNA integration in a hepatocellular carcinoma. Oncogene. 1992; 7: 1653–1656.

    PubMed  CAS  Google Scholar 

  172. Gasparotto D, Maestro R, Piccinin S, et al. Overexpression of CDC25A and CDC25B in head and neck cancers. Cancer Res. 1997; 57: 2366–2368.

    PubMed  CAS  Google Scholar 

  173. Wu W, Fan YH, Kemp BL, Walsh G, Mao L. Overexpression of cdc25A and cdc25B is frequent in primary non-small cell lung cancer but is not associated with overexpression of c-myc. Cancer Res. 1998; 58: 4082–4085.

    PubMed  CAS  Google Scholar 

  174. Meijer L. Chemical inhibitors of cyclin-dependent kinases. Trends Cell Biol. 1996; 6: 393–397.

    Article  PubMed  CAS  Google Scholar 

  175. Fry DW, Kraker AJ, McMichael A, et al. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science. 1994; 265: 1093–1095.

    Article  PubMed  CAS  Google Scholar 

  176. Shimizu E, Zhao MR, Nakanishi H, et al. Differing effects of staurosporine and UCN- 01 on RB protein phosphorylation and expression of lung cancer cell lines. Oncology. 1996; 53: 494–504.

    Article  PubMed  CAS  Google Scholar 

  177. Chang CJ, Gaehlen R. Protein-tyrosine kinase inhibition: mechanism-based discovery of antitumor agents. J Nat Prod. 1992; 55: 1529–1560.

    Article  PubMed  CAS  Google Scholar 

  178. Hidaka H, Kobayashi R. Pharmacology of protein kinase inhibitors. Annu Rev Pharmacol Tociol 1992; 32: 377–397.

    Article  CAS  Google Scholar 

  179. Cui CB, Kakeya H, Osada H. Spirotryprostatin B, a novel mammalian cell cycle inhibitor produced by Aspergillus fumigatus. J Antibiot (Tokyo). 1996; 49: 832–835.

    Article  CAS  Google Scholar 

  180. Kleinberger-Doron N, Shelah N, Capone R, Gazit A, Levitzki A. Inhibition of Cdk2 activation by selected tyrophositins causes cell arrest at late G1 and S phase. Exp Cell Res. 1998; 241: 340–351.

    Article  PubMed  CAS  Google Scholar 

  181. Kitagawa M, Okabe T, Ogino H, et al. Butyrolactone 1A selective inhibitor of CDK2 and CDC2 kinase. Oncogene. 1993; 8: 2425–2432.

    PubMed  CAS  Google Scholar 

  182. Kitagawa M, Higahashi H, Takahashi IS, et al. A cyclin-dependent kinase inhibitor, butyrolactone I, inhibits phosphorylation of RB protein and cell cycle progression. Oncogene. 1994; 9: 2549–2557.

    PubMed  CAS  Google Scholar 

  183. Someya A, Tanaka N, Okuyama A. Inhibition of cell cycle oscillation of DNA replication by a selective inhibitor of the cdc2 kinase family, butyrolactone I, in Xenopus egg extracts. Biochem Biophys Res Commun. 1994; 198: 536–545.

    Article  PubMed  CAS  Google Scholar 

  184. Akagi T, Ono H, Shimotohno K. Tyrosine kinase inhibitor herbimycin A reduces the stability of cyclin-dependent kinase Cdk6 protein in T-cells. Oncogene. 1996; 13: 399–405.

    PubMed  CAS  Google Scholar 

  185. Paull K, Shoemaker RH, Hodes L, et al. Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm. J Natl Cancer Inst. 1989; 81: 1087–1092.

    Article  Google Scholar 

  186. Sedlacek HH, Czech J, Naik R, et al. Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy. Int J Oncol. 1996; 9: 1143–1168.

    PubMed  CAS  Google Scholar 

  187. Rebhun LI, White D, Sander G, Ivy N. Cleavage inhibition in marine eggs by puromycin and 6–dimethylaminopurine. Exp Cell Res. 1973; 77: 312–318.

    Article  PubMed  CAS  Google Scholar 

  188. 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: 377–391.

    Article  Google Scholar 

  189. Norman TC, Gray NS, Koh JT, Schultz PG. A structure-based library approach to kinase inhibitors. J Am Chem Soc. 1996; 118: 7430–7431.

    Article  CAS  Google Scholar 

  190. Gray NS, Kwon S, Schultz PG. Combinatorial synthesis of 2,9–substituted purines. Tetrahedr Lett. 1997; 38: 1161–1164.

    Article  CAS  Google Scholar 

  191. Nugiel DA, Cornelius LAM, Corbett JW. Facile preparation of 2,6–di substituted purines using solid-phase chemistry. J Org Chem. 1997; 62: 201–203.

    Article  PubMed  CAS  Google Scholar 

  192. Imbach P, Capraro HG, Furet P, Mett H, Meyer T, Zimmermann J. 2,6,9–Trisubstituted purines: optimization towards highly potent and selective CDK1 inhibitors. Bioorg Med Chem Lett. 1999; 9: 91–96.

    CAS  Google Scholar 

  193. Havlicek L, Hanus J, Vesely J, et al. Cytokinin-derived cyclin-dependent kinase inhibitors: synthesis and cdc2 inhibitory activity of olomoucine and related compounds. J Med Chem. 1997; 40: 407–411.

    Article  Google Scholar 

  194. Schow SR, Mackman RL, Blum C, et al. Synthesis and activity of 2,6,9–tri substituted purines. Bioorg Med Chem Lett. 1997; 7: 2697–2702.

    Article  CAS  Google Scholar 

  195. Gray NS, Wodicka L, Thunnissen AM, et al. Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science. 1998; 281: 533–538.

    Article  PubMed  CAS  Google Scholar 

  196. 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; 272:29, 207–29, 211.

    Google Scholar 

  197. Vesely J, Havlicek L, Strnad M, et al. Inhibition of cyclin-dependent kinases by purine analogues. Eur J Biochem. 1994; 224: 771–786.

    Article  PubMed  CAS  Google Scholar 

  198. Sedlacek HH, Hoffmann D, Czech J, Kolar C, Seemann G, Gussow D, Bosslet K. Chimia. 1991; 45: 311–316.

    CAS  Google Scholar 

  199. Kaur G, Stetler-Stevenson M, Sebers S, et al. Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86–8275. J Natl Cancer Inst. 1992; 84: 1736–1740.

    Article  PubMed  CAS  Google Scholar 

  200. Losiewicz MD, Carlson BA, Kaur G, Sausville EA, Worland PJ. Potent inhibition of CDC2 kinase activity by the flavonoid L86–8275. Biochem Biophys Res Commun. 1994; 201: 589–595.

    Article  PubMed  CAS  Google Scholar 

  201. Carlson BA, Dubay MM, Sausville EA, Brizuela L, Worland PJ. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res. 1996; 56: 2973–2978.

    PubMed  CAS  Google Scholar 

  202. De Azevedo WF Jr, Mueller-Dieckmann HJ, Schulze-Gahmen U, Worland PJ, Sausville EA, Kim SH. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc Natl Acad Sci USA. 1996; 93: 2735–2740.

    Article  PubMed  Google Scholar 

  203. Kim SH, Schulze-Gahmen U, Brandsen J, de Azevedo WF Jr. Structural basis for chemical inhibition of CDK2. Prog Cell Cycle Res. 1996; 2: 137–145.

    Article  PubMed  CAS  Google Scholar 

  204. Bible KC, Kaufmann SH. Cytotoxic synergy between flavopiridol (NSC 649890, L86–8275) and various antineoplastic agents: the importance of sequence of administration. Cancer Res. 1997; 57: 3375–3380.

    PubMed  CAS  Google Scholar 

  205. Ball KL, Lain S, Fahraeus R, Smythe C, Lane DP. Cell-cycle arrest and inhibition of Cdk4 activity by small peptides based on the carboxy-terminal domain of p212WAF1. Curr Biol. 1997; 7: 71–80.

    Article  PubMed  CAS  Google Scholar 

  206. Chen J, Willingham T, Shuford M, Nisen PD. Tumor suppression and inhibition of aneuploid cell accumulation in human brain tumor cells by ectopic overexpression of the cyclin-dependent kinase inhibitor p27–KIP1. J Clin Invest. 1996; 97: 1983–1988.

    Article  PubMed  CAS  Google Scholar 

  207. Fahraeus R, Paramio JM, Ball KL, Lain S, Lane DP. Inhibition of pRb phosphorylation and cell-cycle progression by a 20–residue peptide derived from p16CDKN2/INK4A. Curr Biol. 1996; 6: 84–91.

    Article  PubMed  CAS  Google Scholar 

  208. 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 

  209. Colas P, Cohen B, Jessen T, Grishina I, McCoy J, Brent R. Genetic selection of peptide aptamers that recognize and inhibit cyclin-dependent kinase 2. Nature. 1996; 380: 547–550.

    Article  Google Scholar 

  210. Cohen BA, Colas P, Brent R. An artificial cell-cycle inhibitor isolated from a combinatorial library. Proc Natl Acad Sci USA. 1998; 95:14, 272–14, 277.

    Google Scholar 

  211. Jin X, Nguyen D, Zhang WW, Kyritsis AP, Roth JA. Cell cycle arrest and inhibition of tumor cell proliferation by the p16INK4 gene mediated by an adenovirus vector. Cancer Res. 1995; 55: 3250–3253.

    PubMed  CAS  Google Scholar 

  212. Yang ZY, Perkins ND, Ohno T, Nabel EG, Nabel GJ. The p21 cyclin-dependent kinase inhibitor suppresses tumorigenicity in vivo. Nat Med. 1995; 1: 1052–1056.

    Article  PubMed  CAS  Google Scholar 

  213. Craig C, Kim M, Ohri E, et al. Effects of adenovirus-mediated p16INK4A expression on cell cycle arrest are determined by endogenous p16 and Rb status in human cancer cells. Oncogene. 1998; 16: 265–272.

    Article  PubMed  CAS  Google Scholar 

  214. Gotoh A, Kao C, Ko SC, Hamada K, Liu TJ, Chung LW. Cytotoxic effects of recombinant adenovirus p53 and cell cycle regulator genes (p21 WAF1/CIP1 and p16CDKNH4) in human prostate cancer. J Urol. 1997; 158: 636–641.

    Article  PubMed  CAS  Google Scholar 

  215. Katayose Y, Kim M, Rakkar AN, Li Z, Cowan KH, Seth P. Promoting apoptosis: a novel activity associated with the cyclin-dependent kinase inhibitor p27. Cancer Res. 1997; 57: 5441–5445.

    PubMed  CAS  Google Scholar 

  216. Wang X, Gorospe M, Huang Y, Holbrook NJ. P27Kip1 overexpression causes apoptitic death of mammalian cells. Oncogene. 1997; 15: 2991–2997.

    Article  PubMed  CAS  Google Scholar 

  217. Rakkar ANS, Li ZW, Katayose Y, Kim M, Cowan KH, Seth P. Adenoviral expression of the cyclin-dependent kinase inhibitor p27 (Kip1): a strategy for breast cancer gene therapy. J Natl Cancer Inst. 1998; 90: 1836–1838.

    Article  PubMed  CAS  Google Scholar 

  218. 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 

  219. Frankel AD, Pabo CO. Cellular uptake of the tat protein from human immunodeficiency virus. Cell. 1988; 55: 1189–1194.

    Article  PubMed  CAS  Google Scholar 

  220. Elliott G, O’Hare P. Intercellular trafficking and protein delivery by a herpesvirus structural protein. Cell. 1997; 88: 223–233.

    Article  PubMed  CAS  Google Scholar 

  221. Derossi D, Joliot AH, Chassaing G, Prochiantz A. The third helix of the Antennapaedia homeodomain translocates through biological membranes. J Biol Chem. 1994; 269:10,444– 10, 450.

    Google Scholar 

  222. Peters KG, Marie J, Wilson E, et al. Point mutation of an FGF receptor abolishes phosphatidylinositol turnover and Ca2+ flux but not mitogenesis. Nature. 1992; 358: 677–681.

    Article  Google Scholar 

  223. Nagahara H, Vocero-Akbani AM, Snyder EL, et al. Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27(Kip1) induces cell migration. Nat Med. 1998; 4: 1449–1452.

    Article  PubMed  CAS  Google Scholar 

  224. Wagner RW. Gene inhibition using antisense oligodeoxynucleotides. Nature 1994; 372: 333–335.

    Article  PubMed  CAS  Google Scholar 

  225. Akiyama T, Yoshida T, Tsujita T, et al. G1 phase accumulation induced by UCN-01 is associated with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/Cip1/WAF1/Sdi1 in p53 mutated human epidermoid carcinoma A431 cells. Cancer Res. 1997; 57: 1495–1501.

    PubMed  CAS  Google Scholar 

  226. Fuse E, Tanii H, Kurata N, et al. Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human alpha1–acid glycoprotein. Cancer Res 1998; 58: 3247–3253.

    Google Scholar 

  227. Senderowicz AM, Headlee D, Lush R, et al. Phase I trial of infusional UCN-01, a novel protein kinase inhibitor, in patients with refractory neoplasms. Proc Amer Soc Clin Oncol. 1999; 18: 612 (a).

    Google Scholar 

  228. Tamura T, Sasaki Y, Minami H, et al. Phase I study of UCN-01 by 3 hours infusion. Proc Amer Soc Clin Oncol 1999; 18: 611 (a).

    Google Scholar 

  229. Senderowicz AM, Headlee D, Stinson SF, et al. Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J Clin Oncol. 1998; 16: 2986–2999.

    PubMed  CAS  Google Scholar 

  230. Stadler WM, Vogelzang NJ, Amato R, et al. Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: a University of Chicago Phase II Consortium Study. J Clin Oncol. 2000; 18: 371.

    PubMed  CAS  Google Scholar 

  231. 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 

  232. Schwartz GK, O’Reilly E, Ilson, et al. Phase I study of the cyclin-dependent kinase inhibitor Flavopiridol in combination with Paclitaxel in patients with advanced solid tumors. J Clin Oncol. 2002; 20: 2157–2170.

    Article  PubMed  CAS  Google Scholar 

  233. Arbuck SG. Paclitaxel: current developmental approaches of the National Cancer Institute. Semin Oncol. 1995; 22: 55–63.

    PubMed  CAS  Google Scholar 

  234. Benson C, Raynaud F, O’Donnell A, et al. Pharmacokinetics (PK) of the oral cyclin dependent kinase inhibitor CYC202 (R-roscovitine) in patients with cancer. Proc Am Assoc Cancer Res. 2002; 273: 1354 (a).

    Google Scholar 

  235. Arris CE, Boyle FT, Calvert AH, et al. Identification of novel purine and pyrimidine cyclindependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J Med Chem. 2000; 43: 2797–2804.

    Article  PubMed  CAS  Google Scholar 

  236. Mani S, Wang C, Wu K, et al. Cyclin-dependent kinase inhibitors: novel anticancer agents. Expert Opin Invest Drugs. 2000; 9: 1849–1870.

    Article  CAS  Google Scholar 

  237. Zöchbauer-Müller S, Minna JD, Gazdar AF. Aberrant DNA methylation in lung cancer: biological and clinical implications. Oncologist. 2002; 7: 451–457.

    Article  PubMed  Google Scholar 

  238. Otterson GA, Khleif SN, Chen W, et al. CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of P16INK4 protein induction by 5’aza-2-deoxycytidine. Oncogene 1995; 11: 1211–1216.

    PubMed  CAS  Google Scholar 

  239. Nuovo GJ, Plaia TW, Belinsky SA, et al. In situ detection of the hypermethylation-induced inactivation of the P16 gene as an early event in oncogenesis. Proc Natl Acad Sci USA 1998; 95:11,891–11,896.

    Google Scholar 

  240. Goffin J, Eisenhauer E. DNA methyltransferase inhibitors-state of the art. Ann Oncol. 2002; 13: 1699–1716.

    Article  PubMed  CAS  Google Scholar 

  241. Kantharidis P, El Osta A, deSilva M, et al. Altered methylation of the human MDR1 promoter is associated with acquired multidrug resistance. Clin Cancer Res. 1997; 3: 2025–2032.

    PubMed  CAS  Google Scholar 

  242. Abele R, Clavel M, Dodion P, et al. The EORTC early clinical trials cooperative group experience with 5–aza-2’-deoxycytidine (NSC 127716) in patients with colo-rectal, head and neck, renal carcinomas and malignat melanomas. Eur J Cancer Clin Oncol. 1987; 23: 1921–1924.

    Article  PubMed  CAS  Google Scholar 

  243. Eisenhauer EA. Phase I and II trials of novel anti-cancer agents: endpoints, efficacy and existentialism. Ann Oncol. 1998; 9: 1047–1052.

    Article  PubMed  CAS  Google Scholar 

  244. Yoshida M, Furumai R, Nishiyama M, et al. Histone deacetylase as a new target for cancer chemotherapy. Cancer Chemother Pharmacol. 2001; 48 (Suppl 1): S20–S26.

    Article  PubMed  CAS  Google Scholar 

  245. Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000; 403: 41–45.

    Article  PubMed  CAS  Google Scholar 

  246. Kuo MH, Allis CD. In vivo cross-linking and immunoprecipitation for studying dynamic protein:DNA associations in a chromatin environment. Methods: Companion Methods Enzymol. 1999; 19: 425–433.

    Article  CAS  Google Scholar 

  247. Fragoso G, Hager GL. Analysis of in vivo nucleosome positions by determination of nucleosome-linker boundaries in crosslinked chromatin. Methods: Companion Methods Enzymol. 1997; 11: 246–252.

    Article  CAS  Google Scholar 

  248. Fry CJ, Peterson CL. Chromatin remodeling enzymes: who’s on first? Current Biol. 2001; 11: R185–197.

    Article  CAS  Google Scholar 

  249. Brownell JE, et al. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell. 1996; 84: 843–851.

    Article  PubMed  CAS  Google Scholar 

  250. Thomson S, Mahadevan LC. Histone acetyltransferases as potential targets for cancer therapies. In: Targets for Cancer Chemotherapy: Transcription Factors and Other Nuclear Proteins. ( La Thangue NB, Bandara LR, eds), Humana Press, Totowa, NJ, 2002; pp. 101–122.

    Chapter  Google Scholar 

  251. Sobulo OM, Borrow J, Tomek R, et al. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3). Proc Natl Acad Sci USA. 1997; 94: 8732–8737.

    Article  PubMed  CAS  Google Scholar 

  252. Lee DH, Goldberg AL. Proteasome inhibitors: valuable new tools for cell biologists. Trends in Cell Biol. 1998; 8: 397–403.

    Article  CAS  Google Scholar 

  253. Myung J, et al. The ubiquitin-proteasome pathway and proteasome inhibitors. Medicinal Res Reviews. 2001; 21: 245–273.

    Article  CAS  Google Scholar 

  254. Kisselev AF, Goldberg AL. Proteasome inhibitors: from research tools to drug candidates. Chem Biol. 2001; 8: 739–758.

    Article  PubMed  CAS  Google Scholar 

  255. Mulligan GJ, D’Cruz C, Kim S, et al. Coordinate regulation of proteasome genes in cancer. Proc Amer Ass Cancer Res. 2002; 1085: 5373 (a).

    Google Scholar 

  256. Mimnaugh EG, Xu W, Isaacs J, et al. Molecular and morphological determinants of the enhanced antiproliferative activity of the novel Hsp90–targeting drug, Geldamycin, combined with the boronated proteasome inhibitor, PS-341. Proc Amer Ass Cancer Res. 2002; 331: 1643 (a).

    Google Scholar 

  257. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 2002; 20:4420– 4427.

    Google Scholar 

  258. Lightcap ES, McCormack TA, Pien CS, et al. Proteasome inhibition measurements: Clinical application. Clin Chem. 2000; 46: 673–683.

    PubMed  CAS  Google Scholar 

  259. Richardson PG, Berenson J, Irwin D, et al. Phase II Study of PS-341, a novel proteasome inhibitor, alone or in combination with dexamethasone in patients with multiple myeloma who have relapsed following front-line therapy and are refractory to their most recent therapy (SUMMIT Trial). Proc Amer Soc Hematol 2002; abstract 3223.

    Google Scholar 

  260. Munemitsu S, et al. Regulation of intracellular-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci USA. 1995; 92: 3046–3050.

    Article  PubMed  CAS  Google Scholar 

  261. Tetsu O, McCormick F. Delta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999; 398: 422–426.

    Article  PubMed  CAS  Google Scholar 

  262. McCormick F. Signalling networks that cause cancer. Trends Cell Biol. 1999; 9: M53–M56.

    Article  PubMed  CAS  Google Scholar 

  263. Keyomarsi K, Tucker SL, Buchholz TA, et al. Cyclin E and survival in patients with breast cancer. New Engl J Med. 2002; 347: 1566–1575.

    Article  CAS  Google Scholar 

  264. Sutherland RL, Musgrove EA. Cyclin E and prognosis in patients with breast cancer. New Engl J Med 2002; 347:1546–1547.

    Google Scholar 

  265. Endicott JA, Noble ME, Tucker JA. Cyclin-dependent kinases: inhibition and substrate recognition. Curr Opin Struct Biol. 1999; 9: 737–744.

    Article  Google Scholar 

  266. Zhu X, Hu C, Zhang Y, Li L, Wang Z. Expression of cyclin-dependent kinase inhibitors, p21cip1 and p27kip1, during wound healing in rats. Wound Repair Regen 2001; 9 (3): 205–212

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  268. Zheleva DI, McInnes C, Gavine AL, et al. 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 

  269. Villacañas 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.

    Article  PubMed  Google Scholar 

  270. Kulkarni MS, Daggett JL, Bender TP, et al. Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis. Leukemia 2002; 16: 127–134.

    Article  PubMed  CAS  Google Scholar 

  271. Lacey KR, Jackson PK, Stearns T. Cyclin-dependent kinase control of centrosome duplication. Proc Natl Acad Sci USA. 1999; 96: 2817–2822.

    Article  PubMed  CAS  Google Scholar 

  272. Chen X, Danes C, Lowe M et al. Activation of the estrogen-signaling pathway by p21WAF1/ CIP1 in estrogen receptor-negative breast cancer cells. J Natl Cancer Inst. 2000; 92: 1403–1413.

    Article  PubMed  CAS  Google Scholar 

  273. Bronchud MH,Scarffe JH,Thatcher N, et al. Phase I/II study of recombinant human granulocyte colony-stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer. Br J Cancer. 1987; 56: 809–813.

    Google Scholar 

  274. Snyder E, Dowdy SF. Reconstitution of tumor suppressor function by in vivo protein and peptide transduction. Proc Amer Assoc Cancer Res. 2002; P. 988: 4897 (a).

    Google Scholar 

  275. Bandara LR, Girling R, La Thangue NB. Apoptosis induced in mammalian cells by small peptides which functionally antagonise the Rb-regulated E2F transcription factor. Nat Biotechnol. 1997; 15: 896–901.

    Article  PubMed  CAS  Google Scholar 

  276. Dobrowolski SF, Stacey DW, Harter ML, et al. An E2F dominant negative mutant blocks E1A induced cell cycle progression. Oncogene 1994; 9: 2605–2612.

    PubMed  CAS  Google Scholar 

  277. Yu X, Guo S, Marcu MG, et al. Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst. 2002; 94: 504–513.

    Article  PubMed  CAS  Google Scholar 

  278. Kaelin WJ. Functions of the retinoblastoma protein. Bioessays. 1999; 21: 950–958.

    Article  PubMed  Google Scholar 

  279. Harbour J, Dean D. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 2000; 14: 2393–2409.

    Article  PubMed  CAS  Google Scholar 

  280. Markey MP, Angus SP, Strobeck MW, et al. Unbiased analysis of Rb-mediated transcriptional repression identifies novel targets and distinctions from E2F action. Cancer Res. 2002; 62: 6587–6597.

    PubMed  CAS  Google Scholar 

  281. Driscoll B, T’Ang A, Hu YH, et al. Discovery of a regulatory motif that controls the exposure of specific upstream cyclin-dependent kinase sites that determine both conformation and growth suppressing activity of pRb. J Biol Chem. 1999; 274: 9463–9471.

    Article  PubMed  CAS  Google Scholar 

  282. Pomerantz J, Schreiber-Agus N, Liegeois NJ, et al. The INK4A tumor suppressor gene product, p19ARF, interacts with MDM2 and neutralizes MDMs’s inhibition of p53. Cell. 1998; 92: 713–723.

    Article  PubMed  CAS  Google Scholar 

  283. Shen Y, White E. p53–Dependent apoptosis pathways. Adv Cancer Res. 2001; 82: 55–84.

    CAS  Google Scholar 

  284. Ho GH, Calvano JE, Bisogna M, et al. Genetic alterations of the p14ARF-hdm2–p53 regulatory pathway in breast carcinoma. Breast Cancer Res Treat. 2001; 65: 225–232.

    Article  PubMed  CAS  Google Scholar 

  285. Shay JW, Zou Y, Hiyama E, et al. Telomerase and cancer. Hum Mol Genet. 2001; 10: 677–685.

    Article  PubMed  CAS  Google Scholar 

  286. Kennedy RD, Quinn JE, Johnston PG, Harkin DP. BRCA1: mechanisms of inactivation and implications for management of patients. Lancet. 2002; 360: 1007–1013.

    Article  PubMed  CAS  Google Scholar 

  287. Furukawa Y, Iwase S, Terui Y, et al. Transcriptional activation of the cdc2 gene is associated with Fas-induced apoptosis of human hematopoietic cells. J Biol Chem. 1996; 271: 28, 469–28, 477.

    Google Scholar 

  288. Vaux DL, Korsmeyer SJ. Cell death in development. Cell. 1999; 96: 245–254

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Miguel H. Bronchud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leonardo Brizuela
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeno Gyuris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Muzammil M. Mansuri
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Medical Oncology, Hospital General de Granollers, Barcelona, Spain

    Miguel H. Bronchud MD, PhD

  2. Amgen Inc., Thousand Oaks, CA, USA

    MaryAnn Foote PhD

  3. Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands

    Giuseppe Giaccone MD, PhD

  4. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA

    Olufunmilayo I. Olopade MBBS

  5. Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, UK

    Paul Workman PhD, FMedSci

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer Science+Business Media New York

About this chapter

Cite this chapter

Bronchud, M.H., Brizuela, L., Gyuris, J., Mansuri, M.M. (2004). Cyclin-Dependent Kinases and Their Regulators as Potential Targets for Anticancer Therapeutics. In: Bronchud, M.H., Foote, M., Giaccone, G., Olopade, O.I., Workman, P. (eds) Principles of Molecular Oncology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-664-5_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-664-5_11

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4757-6276-1

  • Online ISBN: 978-1-59259-664-5

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation