The events of the cell division cycle can be summarized as follows: the G1 cyclins prepare the chromosomes for replication via interactions with corresponding CDKs. A consequent increase in S-phase promoting factors prepares the cell to enter S-phase and duplicate its DNA. As replication continues, one of the cyclins shared by both the G1- and the S-phase CDKs, cyclin E, is destroyed and an increase in M-phase cyclins (cyclins A, B) ensues. M-phase-promoting factors such as cyclins A and B and CDK1 lead to mitotic spindle assembly, breakdown of the nuclear envelope, and chromatin condensation, each of which takes place prior to mitotic anaphase. At this point, the MPF (CDK1/ cyclin B) promotes APC assembly which induces sister chromatid separation and movement to the poles. In order for cells to continue cyclin, phase-specific cyclins must be degraded by the ubiquitin proteasome pathway which targets proteins for destruction by covalent bonding of small ubiquitin molecules permitting their recognition by the protea-some. The INK4 and CIP/KIP families of CDKIs add another level of regulation to the cell cycle. Inhibition of CDK activation through the administration of small-molecule inhibitors is showing promise as a clinical therapeutic strategy through the ability to interrupt CDK enzymatic activity either directly or indirectly.


1. Fattaey, A., and Booher, R. N. (1997). Mytl: a Weel-type kinase that phosphorylates Cdc2 on residue Thr14. Prog Cell Cycle Res

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

3. Muratani, M., and Tansey, W. P. (2003). How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol

4. Polyak, K., Lee M-H, Erdjument-Bromage, H. et al. (1994). Cloning of p21Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 8, 59-66.

5. Murray, A. W. (2004). Recycling the cell cycle: cyclins revisited. Cell 116, 221-234.

6. Lavoie, J. N., L'Allemain, G., Brunet, A., Muller, R., and Pouyssegur, J. (1996). Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/ HOGMAPK pathway. J Biol Chem 271, 20608-20616.

7. Page, K., Li, J., Hodge, J. A. et al. (1999). Characterization of a Rac1 signaling pathway to cyclin D(1) expression in airway smooth muscle cells. J Biol Chem 274, 22065-22071.

8. Lee, R. J., Albanese, C., Fu, M. et al. (2000). Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol 20, 672-683.

9. Lenferink, A. E., Busse, D., Flanagan, W. M., Yakes, F. M., and Arteaga, C. L. (2001). ErbB2/neu kinase modulates cellular p27(Kip1) and cyclin D1 through multiple signaling pathways. Cancer Res 61, 6583-6591.

10. Sclafani, R. A. (1996). Cyclin dependent kinase activating kinases. Curr Opin Cell Biol 8, 788-794.

11. Coleman, T. R., and Dunphy, W. G. (1994). Cdc2 regulatory factors. Curr Opin Cell Biol 6, 877-882.

12. Buschges, R., Weber, R. G., Actor, B. et al. (1999). Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) in human malignant gliomas. Brain Pathol 9, 435-442; discussion 432-433.

13. Lukas, J., Parry, D., Aagaard, L. et al. (1995). Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16. Nature 375, 503-506.

14. Draetta, G. F. (1994). Mammalian G1 cyclins. Curr Opin Cell Biol 6, 842-846.

15. Rane, S. G., Dubus, P., Mettus, R. V. et al. (1999). Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 22, 44-52.

16. Tsutsui, T., Hesabi, B., Moons, D. S. et al. (1999). Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kip1) activity. Mol Cell Biol 19, 7011-7019.

17. Osborne, R. H., Houben, M. P., Tijssen, C. C., Coebergh, J. W., and van Duijn, C. M. (2001). The genetic epidemiology of glioma. Neurology 57, 1751-1755.

18. Behin, A., Hoang-Xuan, K., Carpentier, A. F., and Delattre, J. Y. (2003). Primary brain tumors in adults. Lancet 361, 323-331.

19. Arato-Ohshima, T., and Sawa, H. (1999). Over-expression of cyclin D1 induces glioma invasion by increasing matrix metallo-proteinase activity and cell motility. Int J Cancer 83, 387-392.

20. Sallinen, S. L., Sallinen, P. K., Kononen, J. T. et al. (1999). Cyclin D1 expression in astrocytomas is associated with cell proliferation activity and patient prognosis. J Pathol 188, 289-293.

21. Allan, K., Jordan, R. C., Ang, L. C., Taylor, M., and Young, B. (2000). Overexpression of cyclin A and cyclin B1 proteins in astrocytomas. Arch Pathol Lab Med 124, 216-220.

22. Dyson N. (1994). pRB, p107 and the regulation of the E2F transcription factor. J Cell Sci Suppl 18, 81-87.

23. Flemington, E. K., Speck, S. H., and Kaelin, W. G. Jr. (1993). E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product. Proc Natl Acad Sci U S A 90, 6914-6918.

24. Ortega, S., Malumbres, M., and Barbacid, M. (2002). Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta 1602, 73-87.

25. Hannon, G. J., and Beach, D. (1994). p15 is a potential effector of cell cycle arrest mediated by TGF beta. Nature 371, 257-261.

26. Watanabe, T., Nakamura, M., Yonekawa, Y., Kleihues, P., and Ohgaki, H. (2001). Promoter hypermethylation and homozygous deletion of the p14ARF and p16INK4a genes in oligodendrogliomas. Acta Neuropathol (Berl) 101, 185-189.

27. Watanabe, T., Yokoo, H., Yokoo, M., Yonekawa, Y., Kleihues, P., and Ohgaki, H. (2001). Concurrent inactivation of RB1 and TP53 pathways in anaplastic oligodendrogliomas. J Neuropathol Exp Neurol 60, 1181-1189.

28. Herman, J. G., Jen, J., Merlo, A., and Baylin, S. B. (1996). Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res 56, 722-727.

29. Fuxe, J., Akusjarvi, G., Goike, H. M., Roos, G., Collins, V. P., and Pettersson, R. F. (2000). Adenovirus-mediated overexpression of p15INK4B inhibits human glioma cell growth, induces replicative senescence, and inhibits telomerase activity similarly to p16INK4A. Cell Growth Differ 11, 373-384.

30. Duro, D., Bernard, O., Della Valle, V., Berger, R., and Larsen, C. J. (1995). A new type of p16INK4/MTS1 gene transcript expressed in B-cell malignancies. Oncogene 11, 21-29.

31. Quelle, D. E., Zindy, F., Ashmun, R. A., and Sherr, C. J. (1995). Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83, 993-1000.

32. Stone, S., Jiang, P., Dayananth, P., Tavtigian, S. V., Katcher, H., Parry, D., Peters, G., and Kamb, A. (1995). Complex structure and regulation of the P16 (MTS1) locus. Cancer Res 55, 2988-2994.

33. Serrano, M., Lee, H. W., Chin, L., and Cordon-Cardo, C. (1996). Role of the INK4 locus in tumor suppression and cell mortality. Cell 85, 27-37.

34. Kamijo, T., Zindy, F., Roussel, M. F. et al. (1997). Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649-659.

35. Krimpenfort, P., Quon, K. C., Mooi, W. J., Loonstra, A., and Berns, A. (2001). Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 413, 83-86.

36. Sharpless, N. E., Bardeesy, N., Lee, K. H. et al. (2001). Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86-91.

37. Kamijo, T., Bodner, S., van de Kamp, E., Randle, D. H., and Sherr, C. J. (1999). Tumor spectrum in ARF-deficient mice. Cancer Res 59, 2217-2222.

38. Sharpless, N. E., Ramsey, M. R., Balasubramanian, P., Castrillon, D. H., and DePinho, R. A. (2004). The differential impact of p16(INK4a) or p19(ARF) deficiency on cell growth and tumorigenesis. Oncogene 23, 379-385.

39. Holland, E. C., Hively, W. P., DePinho, R. A., and Varmus, H. E. (1998). A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev 12, 3675-3685.

40. Holland, E. C., Celestino, J., Dai, C., Schaefer, L., Sawaya, R. E., and Fuller, G. N. (2000). Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25, 55-57.

41. Zindy, F., van Deursen, J., Grosveld, G., Sherr, C. J., and Roussel, M. F. (2000). INK4d-deficient mice are fertile despite testicular atrophy. Mol Cell Biol 20, 372-378.

42. Franklin, D. S., Godfrey, V. L., Lee, H. et al. (1998). CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes Dev 12, 2899-2911.

43. Pei, X. H., Bai, F., Tsutsui, T., Kiyokawa, H., and Xiong, Y. (2004). Genetic evidence for functional dependency of p18Ink4c on Cdk4. Mol Cell Biol 24, 6653-6664.

44. Harper, J. W., Adami, G. R., Wei, N., Keyomarsi, K., and Elledge, S. J. (1993). The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75, 805-816.

45. el-Deiry, W. S., Tokino, T., Velculescu, V. E. et al. (1993). WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817-825.

46. Cox, L. S. (1997). Multiple pathways control cell growth and transformation: overlapping and independent activities of p53 and p21Cip1/WAF1/Sdi1. J Pathol 183, 134-140.

47. LaBaer, J., Garrett, M. D., Stevenson, L. F. et al. (1997). New functional activities for the p21 family of CDK inhibitors. Genes Dev 11, 847-862.

48. Cheng, M., Olivier, P., Diehl, J. A. et al. (1999). The p21(Cip1) and p27(Kip1) CDK "inhibitors" are essential activators of cyclin D-dependent kinases in murine fibroblasts. Embo J 18, 1571-1583.

49. Cheng, M., Sexl, V., Sherr, C. J., and Roussel, M. F. (1998). Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1). Proc Natl Acad Sci U S A 95, 1091-1096.

50. Deng, C., Zhang, P., Harper, J. W., Elledge, S. J., and Leder, P.

(1995). Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82, 675-684.

51. Kiyokawa, H., Kineman, R. D., Manova-Todorova, K. O. et al.

(1996). Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell 85, 721-732.

52. Fero, M. L., Rivkin, M., Tasch, M. et al. (1996). A syndrome of multiorgan hyperplasia with features of gigantism, tumorigen-esis, and female sterility in p27(Kip1)-deficient mice. Cell 85, 733-744.

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

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

55. Alt, J. R., Gladden, A. B., and Diehl, J. A. (2002). p21(Cip1) Promotes cyclin D1 nuclear accumulation via direct inhibition of nuclear export. J Biol Chem 277, 8517-8523.

56. Alt, J. R., Cleveland, J. L., Hannink, M., and Diehl, J. A. (2000). Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev 14, 3102-3114.

57. Ohtsubo, M., Theodoras, A. M., Schumacher, J., Roberts, J. M., and Pagano, M. (1995). Human cyclin, E., a nuclear protein essential for the G1-to-S-phase transition. Mol Cell Biol 15, 2612-2624.

58. Montagnoli, A., Fiore, F., Eytan, E. et al. (1999). Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. Genes Dev 13, 1181-1189.

59. Shirane, M., Harumiya, Y., Ishida, N. et al. (1999). Down-regulation of p27(Kip1) by two mechanisms, ubiquitin-mediated degradation and proteolytic processing. J Biol Chem 274, 13886-13893.

60. Tsvetkov, L. M., Yeh, K. H., Lee, S. J., Sun, H., and Zhang, H.

(1999). p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27. Curr Biol 9, 661-664.

61. Deng, X., Mercer, S. E., Shah, S., Ewton, D. Z., and Friedman, E. (2004). The cyclin-dependent kinase inhibitor p27Kip1 is stabilized in G(0) by Mirk/dyrk1B kinase. J Biol Chem 279, 22498-22504.

62. Zeng, Y., Hirano, K., Hirano, M., Nishimura, J., and Kanaide, H.

(2000). Minimal requirements for the nuclear localization of p27(Kip1), a cyclin-dependent kinase inhibitor. Biochem Biophys Res Commun 274, 37-42.

63. Sheaff, R. J., Groudine, M., Gordon, M., Roberts, J. M., and Clurman, B. E. (1997). Cyclin E-CDK2 is a regulator of p27Kip1. Genes Dev 11, 1464-1478.

64. Malek, N. P., Sundberg, H., McGrew, S., Nakayama, K., Kyriakides, T. R., Roberts, J. M., and Kyriakidis, T. R. (2001). A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S-phase. Nature 413, 323-327.

65. Brugarolas, J., Chandrasekaran, C., Gordon, J. I. et al. (1995). Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377, 552-557.

66. Kirla, R. M., Haapasalo, H. K., Kalimo, H., and Salminen, E. K. (2003). Low expression of p27 indicates a poor prognosis in patients with high-grade astrocytomas. Cancer 97, 644-648.

67. Tamiya, T., Mizumatsu, S., Ono, Y. et al. (2001). High cyclin E/low p27Kip1 expression is associated with poor prognosis in astrocytomas. Acta Neuropathol (Berl) 101, 334-340.

68. Sherr, C. J., and Weber, J. D. (2000). The ARF/p53 pathway. Curr Opin Genet Dev 10, 94-99.

69. Taylor, W. R., and Stark, G. R. (2001). Regulation of the G2/M transition by p53. Oncogene 20, 1803-1815.

70. Schwartz, D., and Rotter, V. (1998). p53-dependent cell cycle control: response to genotoxic stress. Semin Cancer Biol 8, 325-336.

71. Kamijo, T., Weber, J. D., Zambetti, G. et al. (1998). Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci USA 95, 8292-8297.

72. Sherr, C. J., and Roberts, J. M. (1999). CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13, 1501-1512.

73. Hatakeyama, M., Brill, J. A., Fink, G. R., and Weinberg, R. A. (1994). Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. Genes Dev 8, 1759-1771.

74. Mittnacht, S., Lees, J. A., Desai, D., Harlow, E., Morgan, D. O., and Weinberg, R. A. (1994). Distinct sub-populations of the retinoblastoma protein show a distinct pattern of phosphorylation. Embo J 13, 118-127.

75. Alexander, K., and Hinds, P. W. (2001). Requirement for p27(KIP1) in retinoblastoma protein-mediated senescence. Mol Cell Biol 21, 3616-3631.

76. Koff, A., Giordano, A., Desai, D. et al. (1992). Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science 257, 1689-1694.

77. van den Heuvel, S., and Harlow, E. (1993). Distinct roles for cyclin-dependent kinases in cell cycle control. Science 262, 2050-2054.

78. Jiang, H., Chou, H. S., and Zhu L. (1998). Requirement of cyclin E-Cdk2 inhibition in p16(INK4a)-mediated growth suppression. Mol Cell Biol 18, 5284-5290.

79. Nigg, E. A. (2001). Cell cycle regulation by protein kinases and phosphatases. Ernst Schering Res Found Workshop, 19-46.

80. Kramer, A., Mailand, N., Lukas, C. et al. (2004). Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase. Nat Cell Biol 6, 884-891.

81. Castedo, M., Perfettini, J. L., Roumier, T., and Kroemer, G. (2002). Cyclin-dependent kinase-1: linking apoptosis to cell cycle and mitotic catastrophe. Cell Death Differ 9, 1287-1293.

82. Waizenegger, I., Gimenez-Abian, J. F., Wernic, D., and Peters, J. M. (2002). Regulation of human separase by securin binding and autocleavage. Curr Biol 12, 1368-1378.

83. Kotani, S., Tanaka, H., Yasuda, H., and Todokoro, K. (1999). Regulation of APC activity by phosphorylation and regulatory factors. J Cell Biol 146, 791-800.

84. Kraft, C., Herzog, F., Gieffers, C. et al. (2003). Mitotic regulation of the human anaphase-promoting complex by phosphoryla-tion. Embo J 22, 6598-6609.

85. Peters, J. M. (2002). The anaphase-promoting complex: proteolysis in mitosis and beyond. Mol Cell 9, 931-943.

86. Nasmyth K. (2002). Segregating sister genomes: the molecular biology of chromosome separation. Science 297, 559-565.

87. Reimann, J. D., Gardner, B. E., Margottin-Goguet, F., and Jackson, P. K. (2001). Emi1 regulates the anaphase-promoting complex by a different mechanism than Mad2 proteins. Genes Dev 15, 3278-3285.

88. Reimann, J. D., Freed, E., Hsu, J. Y., Kramer, E. R., Peters, J. M., and Jackson, P. K. (2001). Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex. Cell 105, 645-655.

89. Hsu, J. Y., Reimann, J. D., Sorensen, C. S., Lukas, J., and Jackson, P. K. (2002). E2F-dependent accumulation of hEmi1 regulates S-phase entry by inhibiting APC(Cdh1). Nat Cell Biol 4, 358-366.

90. Margottin-Goguet, F., Hsu, J. Y., Loktev, A., Hsieh, H. M., Reimann, J. D., and Jackson, P. K. (2003). Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase. Dev Cell 4, 813-826.

91. Zachariae, W., Shevchenko, A., Andrews, P. D. et al. (1998). Mass spectrometric analysis of the anaphase-promoting complex from yeast: identification of a subunit related to cullins. Science 279, 1216-1219.

92. Jaspersen, S. L., Charles, J. F., and Morgan, D. O. (1999). Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14. Curr Biol 9, 227-236.

93. Acquaviva, C., Herzog, F., Kraft, C., and Pines, J. (2004). The anaphase promoting complex/cyclosome is recruited to centromeres by the spindle assembly checkpoint. Nat Cell Biol 6, 892-898.

94. Song, M. S., and Lim, D. S. (2004). Control of APC-Cdc20 by the tumor suppressor RASSF1A. Cell Cycle 3, 574-576.

95. Hoque, M. T., and Ishikawa, F. (2001). Human chromatid cohesin component hRad21 is phosphorylated in M-phase and associated with metaphase centromeres. J Biol Chem 276, 5059-5067.

96. Blanco, M. A., Sanchez-Diaz, A., de Prada, J. M., and Moreno, S. (2000). APC(ste9/srw1) promotes degradation of mitotic cyclins in G(1) and is inhibited by cdc2 phosphorylation. Embo J 19, 3945-3955.

97. Pfleger, C. M., Lee, E., and Kirschner, M. W. (2001). Substrate recognition by the Cdc20 and Cdh1 components of the anaphase-promoting complex. Genes Dev 15, 2396-2407.

98. Gieffers, C., Peters, B. H., Kramer, E. R., Dotti, C. G., and Peters, J. M. (1999). Expression of the CDH1-associated form of the anaphase-promoting complex in postmitotic neurons. Proc Natl Acad Sci USA 96, 11317-11322.

99. Senderowicz, A. M., and Sausville, E. A. (2000). RESPONSE: re: preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst 92, 1185.

100. Chen, W., Lee, J., Cho, S. Y., and Fine, H. A. (2004). Proteasome-mediated destruction of the cyclin a/cyclin-dependent kinase 2 complex suppresses tumor cell growth in vitro and in vivo. Cancer Res 64, 3949-3957.

101. De Azevedo, W. F., Leclerc, S., Meijer, L., Havlicek, L., Strnad, M., and Kim, S. H. (1997). Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine. Eur J Biochem 243, 518-526.

102. Meijer, L., and Kim, S. H. (1997). Chemical inhibitors of cyclin-dependent kinases. Methods Enzymol 283, 113-128.

103. Zaharevitz, D. W., Gussio, R., Leost, M. et al. (1999). Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. Cancer Res 59, 2566-2569.

104. Knockaert, M., Greengard, P., and Meijer, L. (2002). Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci 23, 417-425.

105. Vesely, J., Havlicek, L., Strnad, M. et al. (1994). Inhibition of cyclin-dependent kinases by purine analogues. Eur J Biochem 224, 771-786.

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

107. Havlicek, L., Hanus, J., Vesely, J. et al. (1997). Cytokinin-derived cyclin-dependent kinase inhibitors: synthesis and cdc2 inhibitory activity of olomoucine and related compounds. J Med Chem 40, 408-412.

108. Gray, N. S., Wodicka, L., Thunnissen, A. M. et al. (1998). Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science 281, 533-538.

109. Abraham, R. T., Acquarone, M., Andersen, A. et al. (1995). Cellular effects of olomoucine, an inhibitor of cyclin-dependent kinases. Biol Cell 83, 105-120.

110. Kwon, Y. G., Lee, S. Y., Choi, Y., Greengard, P., and Nairn, A. C. (1997). Cell cycle-dependent phosphorylation of mammalian protein phosphatase 1 by cdc2 kinase. Proc Natl Acad Sci U S A 94, 2168-2173.

111. Kim, E. H., Kim, S. U., Shin, D. Y., and Choi, K. S. (2004). Roscovitine sensitizes glioma cells to TRAIL-mediated apoptosis by downregulation of survivin and XIAP. Oncogene 23, 446-456.

112. Ljungman, M., and Paulsen, M. T. (2001). The cyclin-dependent kinase inhibitor roscovitine inhibits RNA synthesis and triggers nuclear accumulation of p53 that is unmodified at Ser15 and Lys382. Mol Pharmacol 60, 785-789.

113. Lu, W., Chen, L., Peng, Y., and Chen, J. (2001). Activation of p53 by roscovitine-mediated suppression of MDM2 expression. Oncogene 20, 3206-3216.

114. Eshleman, J. S., Carlson, B. L., Mladek, A. C., Kastner, B. D., Shide, K. L, and Sarkaria, J. N. (2002). Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 62, 7291-7297.

115. De Azevedo, W. F., Jr., Mueller-Dieckmann, H. J., Schulze-Gahmen, U., Worland, P. J., Sausville, E., and Kim, S. H. (1996). Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc Natl Acad Sci U S A 93, 2735-2740.

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

117. Worland, P. J., Kaur, G., Stetler-Stevenson, M., Sebers, S., Sartor, O., and Sausville, E. A. (1993). Alteration of the phosphorylation state of p34cdc2 kinase by the flavone L86-8275 in breast carcinoma cells. Correlation with decreased H1 kinase activity. Biochem Pharmacol 46, 1831-1840.

118. Losiewicz, M. D., Carlson, B. A., Kaur, G., Sausville, E. A., and Worland, P. J. (1994). Potent inhibition of CDC2 kinase activity by the flavonoid L86-8275. Biochem Biophys Res Commun 201, 589-595.

119. Carlson, B. A., Dubay, M. M., Sausville, E. A., Brizuela, L., and Worland, P. J. (1996). Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res 56, 2973-2978.

120. Dai, Y., and Grant S. (2003). Cyclin-dependent kinase inhibitors. Curr Opin Pharmacol 3, 362-370.

121. Chao, S. H., Fujinaga, K., Marion, J. E. et al. (2000). Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J Biol Chem 275, 28345-28348.

122. Chao, S. H., and Price, D. H. (2001). Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem 276, 31793-31799.

123. de Azevedo, W. F., Jr., Canduri, F., and da Silveira, N. J. (2002). Structural basis for inhibition of cyclin-dependent kinase 9 by flavopiridol. Biochem Biophys Res Commun 293, 566-571.

124. Senderowicz, A. M. (2001). Development of cyclin-dependent kinase modulators as novel therapeutic approaches for hematological malignancies. Leukemia 15, 1-9.

125. Zhai, S., Senderowicz, A. M., Sausville, E. A., and Figg, W. D. (2002). Flavopiridol, a novel cyclin-dependent kinase inhibitor, in clinical development. Ann Pharmacother 36, 905-911.

126. Lam, L. T., Pickeral, O. K., Peng, A. C. et al. (2001). Genomic-scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol. Genome Biol 2, RESEARCH0041.

127. Burdette-Radoux, S., Tozer, R. G., Lohmann, R. C. et al. (2004). Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma. Invest New Drugs 22, 315-322.

128. Liu, G., Gandara, D. R., Lara, P. N. et al. (2004). A Phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer. Clin Cancer Res 10, 924-928.

129. Alonso, M., Tamasdan, C., Miller, D. C., and Newcomb, E. W. (2003). Flavopiridol induces apoptosis in glioma cell lines independent of retinoblastoma and p53 tumor suppressor pathway alterations by a caspase-independent pathway. Mol Cancer Ther 2, 139-150.

130. Pepper, C., Thomas, A., Hoy, T., Fegan, C., and Bentley, P. (2001). Flavopiridol circumvents Bcl-2 family mediated inhibition of apoptosis and drug resistance in B-cell chronic lymphocytic leukaemia. Br J Haematol 114, 70-77.

131. Li, W., Fan, J., and Bertino, J. R. (2001). Selective sensitization of retinoblastoma protein-deficient sarcoma cells to doxorubicin by flavopiridol-mediated inhibition of cyclin-dependent kinase 2 kinase activity. Cancer Res 61, 2579-2582.

132. Colevas, D., Blaylock, B., and Gravell A. (2002). Clinical trials referral resource. Flavopiridol. Oncology (Huntingt) 16, 1204-1205, 1210-1212, 1214.

133. Schwartz, G. K., Ilson, D., Saltz, L. et al. (2001). Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. J Clin Oncol 19, 1985-1992.

134. Karp, J. E., Ross, D. D., Yang, W. et al. (2003). Timed sequential therapy of acute leukemia with flavopiridol: in vitro model for a phase I clinical trial. Clin Cancer Res 9, 307-315.

135. Schwartz, G. K., O'Reilly, E., Ilson, D. et al. (2002). Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors. J Clin Oncol 20, 2157-2170.

136. Matranga, C. B., and Shapiro, G. I. (2002). Selective sensitization of transformed cells to flavopiridol-induced apoptosis following recruitment to S-phase. Cancer Res 62, 1707-1717.

137. Cartee, L., Wang, Z., Decker, R. H. et al. (2001). The cyclin-dependent kinase inhibitor (CDKI) flavopiridol disrupts phorbol 12-myristate 13-acetate-induced differentiation and CDKI expression while enhancing apoptosis in human myeloid leukemia cells. Cancer Res 61, 2583-2591.

138. Robey, R. W., Medina-Perez, W. Y., Nishiyama, K. et al. (2001). Overexpression of the ATP-binding cassette half-transporter, ABCG2 (Mxr/BCrp/ABCP1), in flavopiridol-resistant human breast cancer cells. Clin Cancer Res 7, 145-152.

139. Smith, V., Raynaud, F., Workman, P., and Kelland, L. R. (2001). Characterization of a human colorectal carcinoma cell line with acquired resistance to flavopiridol. Mol Pharmacol 60, 885-893.

140. Boerner, S. A., Tourne, M. E., Kaufmann, S. H., and Bible, K. C. (2001). Effect of P-glycoprotein on flavopiridol sensitivity. Br J Cancer 84, 1391-1396.

141. Senderowicz, A. M., Headlee, D., Stinson, S. F. et al. (1998). Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J Clin Oncol 16, 2986-2999.

142. Tan, A. R., Headlee, D., Messmann, R. et al. (2002). Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms. J Clin Oncol 20, 4074-4082.

143. Tan, A. R., Yang, X., Berman, A. et al. (2004). Phase I trial of the cyclin-dependent kinase inhibitor flavopiridol in combination with docetaxel in patients with metastatic breast cancer. Clin Cancer Res 10, 5038-5047.

144. Komander, D., Kular, G. S., Bain, J., Elliott, M., Alessi, D. R., and Van Aalten, D. M. (2003). Structural basis for UCN-01 (7-hydroxystaurosporine) specificity and PDK1 (3-phosphoinosi-tide-dependent protein kinase-1) inhibition. Biochem J 375, 255-262.

145. Akinaga, S., Gomi, K., Morimoto, M., Tamaoki, T., and Okabe, M. (1991). Antitumor activity of UCN-01, a selective inhibitor of protein kinase, C., in murine and human tumor models. Cancer Res 51, 4888-4892.

146. Akinaga, S., Nomura, K., Gomi, K., and Okabe, M. (1994). Effect of UCN-01, a selective inhibitor of protein kinase, C., on the cell-cycle distribution of human epidermoid carcinoma, A431 cells. Cancer Chemother Pharmacol 33, 273-280.

147. Seynaeve, C. M., Stetler-Stevenson, M., Sebers, S., Kaur, G., Sausville, E. A., and Worland, P. J. (1993). Cell cycle arrest and growth inhibition by the protein kinase antagonist UCN-01 in human breast carcinoma cells. Cancer Res 53, 2081-2086.

148. Wang, Q., Worland, P. J., Clark, J. L., Carlson, B. A., and Sausville, E. A. (1995). Apoptosis in 7-hydroxystaurosporine-treated T lymphoblasts correlates with activation of cyclin-dependent kinases 1 and 2. Cell Growth Differ 6, 927-936.

149. Akiyama, T., Yoshida, T., Tsujita, T. et al. (1997). G1 phase accumulation induced by UCN-01 is associated with depho-sphorylation 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 57, 1495-1501.

150. Patel, V., Lahusen, T., Leethanakul, C. et al. (2002). Antitumor activity of UCN-01 in carcinomas of the head and neck is associated with altered expression of cyclin D3 and p27(KIP1). Clin Cancer Res 8, 3549-3560.

151. Yamasaki, F., Hama, S., Yoshioka, H. et al. (2003). Staurosporine-induced apoptosis is independent of p16 and p21 and achieved via arrest at G2/M and at G1 in U251MG human glioma cell line. Cancer Chemother Pharmacol 51, 271-283.

152. Facchinetti, M. M., De Siervi, A., Toskos, D., and Senderowicz, A. M. (2004). UCN-01-induced cell cycle arrest requires the transcriptional induction of p21(waf1/cip1) by activation of mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway. Cancer Res 64, 3629-3637.

153. Wang, Q., Fan, S., Eastman, A., Worland, P. J., Sausville, E. A., and O'Connor, P. M. (1996). UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J Natl Cancer Inst 88, 956-965.

154. Sausville, E. A., Arbuck, S. G., Messmann, R. et al. (2001). Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms. J Clin Oncol 19, 2319-2333.

155. Sausville, E. A. (2003). Cyclin-dependent kinase modulators studied at the NCI: pre-clinical and clinical studies. Curr Med Chem Anti-Canc Agents 3, 47-56.

156. Bunch, R. T., and Eastman, A. (1996). Enhancement of cisplatin-induced cytotoxicity by 7-hydroxystaurosporine (UCN-01), a new G2-checkpoint inhibitor. Clin Cancer Res 2, 791-797.

157. Pollack, I. F., Kawecki, S., and Lazo, J. S. (1996). Blocking of glioma proliferation in vitro and in vivo and potentiating the effects of BCNU and cisplatin: UCN-01, a selective protein kinase C inhibitor. J Neurosurg 84, 1024-1032.

158. Husain, A., Yan, X. J., Rosales, N., Aghajanian, C., Schwartz, G. K., and Spriggs, D. R. (1997). UCN-01 in ovary cancer cells: effective as a single agent and in combination with cis-diamminedichloroplatinum(II)independent of p53 status. Clin Cancer Res 3, 2089-2097.

159. Shao, R. G., Shimizu, T., and Pommier, Y. (1997). 7-Hydro-xystaurosporine (UCN-01) induces apoptosis in human colon carcinoma and leukemia cells independently of p53. Exp Cell Res 234, 388-397.

160. Tsuchida, E., and Urano, M. (1997). The effect of UCN-01 (7-hydroxystaurosporine), a potent inhibitor of protein kinase, C., on fractionated radiotherapy or daily chemotherapy of a murine fibrosarcoma. Int J Radiat Oncol Biol Phys 39, 1153-1161.

161. Hsueh, C. T., Kelsen, D., and Schwartz, G. K. (1998). UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in a sequence-dependent manner. Clin Cancer Res 4, 2201-2206.

162. Jones, C. B., Clements, M. K., Redkar, A., and Daoud, S. S. (2000). UCN-01 and camptothecin induce DNA double-strand breaks in p53 mutant tumor cells, but not in normal or p53 negative epithelial cells. Int J Oncol 17, 1043-1051.

163. Sugiyama, K., Shimizu, M., Akiyama, T. et al. (2000). UCN-01 selectively enhances mitomycin C cytotoxicity in p53 defective cells which is mediated through S and/or G(2) checkpoint abrogation. Int J Cancer 85, 703-709.

164. Monks, A., Harris, E. D., Vaigro-Wolff, A., Hose, C. D., Connelly, J. W., and Sausville, E. A. (2000). UCN-01 enhances the in vitro toxicity of clinical agents in human tumor cell lines. Invest New Drugs 18, 95-107.

165. Harvey, S., Decker, R., Dai, Y. et al. (2001). Interactions between 2-fluoroadenine 9-beta-D-arabinofuranoside and the kinase inhibitor UCN-01 in human leukemia and lymphoma cells. Clin Cancer Res 7, 320-330.

166. Scovassi, A. I., Stivala, L. A., Rossi, L., Bianchi, L., and Prosperi, E. (1997). Nuclear association of cyclin D1 in human fibroblasts: tight binding to nuclear structures and modulation by protein kinase inhibitors. Exp Cell Res 237, 127-134.

167. Haddad, R. I., Weinstein, L. J., Wieczorek, T. J. et al. (2004). A phase II clinical and pharmacodynamic study of E7070 in patients with metastatic, recurrent, or refractory squamous cell carcinoma of the head and neck: modulation of retinoblastoma protein phosphorylation by a novel chloroin-dolyl sulfonamide cell cycle inhibitor. Clin Cancer Res 10, 4680-4687.

168. Imajoh-Ohmi, S., Kawaguchi, T., Sugiyama, S. et al. (1995). Lactacystin, a specific inhibitor of the proteasome, induces apoptosis in human monoblast U937 cells. Biochem Biophys Res Commun 217, 1070-1077.

169. Fujita, E., Mukasa, T., Tsukahara, T., Arahata, K., Omura, S., and Momoi, T. (1996). Enhancement of CPP32-like activity in the TNF-treated U937 cells by the proteasome inhibitors. Biochem Biophys Res Commun 224, 74-79.

170. Kitagawa, H., Tani, E., Ikemoto, H., Ozaki, I., Nakano, A., and Omura, S. (1999). Proteasome inhibitors induce mitochondria-independent apoptosis in human glioma cells. FEBS Lett 443, 181-186.

171. Wagenknecht, B., Hermisson, M., Eitel, K., and Weller, M. (1999). Proteasome inhibitors induce p53/p21-independent apoptosis in human glioma cells. Cell Physiol Biochem 9, 117-125.

172. Tani, E., Kitagawa, H., Ikemoto, H., and Matsumoto, T. (2001). Proteasome inhibitors induce Fas-mediated apoptosis by c-Myc accumulation and subsequent induction of FasL message in human glioma cells. FEBS Lett 504, 53-58.

173. Orlowski, R. Z., Eswara, J. R., Lafond-Walker, A. et al. (1998). Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor. Cancer Res 58, 4342-4348.

174. Adams, J., and Elliott, P. J. (2000). New agents in cancer clinical trials. Oncogene 19, 6687-6692.

175. Sunwoo, J. B., Chen, Z., Dong, G. et al. (2001). Novel pro-teasome inhibitor PS-341 inhibits activation of nuclear factor-kappa, B., cell survival, tumor growth, and angiogen-esis in squamous cell carcinoma. Clin Cancer Res 7, 1419-1428.

176. Masdehors, P., Omura, S., Merle-Beral, H. et al. (1999). 185. Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor 186. lactacystin. Br J Haematol 105, 752-757.

177. Soligo, D., Servida, F., Delia, D., et al. (2001). The apoptogenic response of human myeloid leukaemia cell lines and of normal and malignant haematopoietic progenitor cells to the 187. proteasome inhibitor PSI. Br J Haematol 113, 126-135.

178. Hideshima, T., Chauhan, D., Podar, K., Schlossman, R. L., Richardson, P., and Anderson, K. C. (2001). Novel therapies targeting the myeloma cell and its bone marrow microenvir- 188. onment. Semin Oncol 28, 607-612.

179. Guzman, M. L., Swiderski, C. F., Howard, D. S. et al. (2002). Preferential induction of apoptosis for primary human 189. leukemic stem cells. Proc Natl Acad Sci U S A 99, 16220-16225.

180. Teicher, B. A., Ara, G., Herbst, R., Palombella, V. J., and Adams, J. (1999). The proteasome inhibitor PS-341 in cancer 190. therapy. Clin Cancer Res 5, 2638-2645.

181. Maki, C. G., Huibregtse, J. M., and Howley, P. M. (1996). In 191. vivo ubiquitination and proteasome-mediated degradation of p53(1). Cancer Res 56, 2649-2654.

182. Hateboer, G., Kerkhoven, R. M., Shvarts, A., Bernards, R., Beijersbergen, R. L. (1996). Degradation of E2F by the 192. ubiquitin-proteasome pathway: regulation by retinoblastoma family proteins and adenovirus transforming proteins. Genes Dev 10, 2960-2970.

183. Wagenknecht, B., Hermisson, M., Groscurth, P., Liston, P., Krammer, P. H., and Weller, M. (2000). Proteasome inhibitor- 193. induced apoptosis of glioma cells involves the processing of multiple caspases and cytochrome c release. J Neurochem 75, 2288-2297. 194.

184. Kudo, Y., Takata, T., Ogawa, I. et al. (2000). p27Kip1 accumulation by inhibition of proteasome function induces apoptosis in oral squamous cell carcinoma cells. Clin Cancer Res 6, 916-923.

Park, D. J., and Lenz, H. J. (2004). The role of proteasome inhibitors in solid tumors. Ann Med 36, 296-303. Aghajanian, C., Soignet, S., Dizon, D. S. et al. (2002). A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 8, 2505-2511.

Orlowski, R. Z., Stinchcombe, T. E., Mitchell, B. S. et al. (2002). Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20, 4420-4427.

Richardson, P. G., Barlogie, B., Berenson, J. et al. (2003). A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348, 2609-2617.

Goy, A., and Gilles, F. (2004). Update on the proteasome inhibitor bortezomib in hematologic malignancies. Clin Lymphoma 4, 230-237.

Lenz, H. J. (2003). Clinical update: proteasome inhibitors in solid tumors. Cancer Treat Rev. 29 Suppl 1, 41-48. Chauhan, D., Li, G., Podar, K. et al. (2004). The bortezomib/ proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance. Blood 103, 3158-3166. Mitsiades, N., Mitsiades, C. S., Richardson, P. G. et al. (2003). The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemo-therapeutic agents: therapeutic applications. Blood 101, 2377-2380.

Bayes, M., Rabasseda, X., and Prous, J. R. (2004). Gateways to clinical trials. Methods Find Exp Clin Pharmacol 26, 211-244.

Kamat, A. M., Karashima, T., Davis, D. W. et al. (2004). The proteasome inhibitor bortezomib synergizes with gemci-tabine to block the growth of human 253JB-V bladder tumors in vivo. Mol Cancer Ther 3, 279-290.

PLATE 9.2 (Fig. 9.2)

cdc25A phosphatase PLATE 9.3 (Fig. 9.3)

PLATE 9.4 (Fig. 9.4)
PLATE 9.6 (Fig. 9.6)
10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

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