Targeting the Cell Cycle for Cancer Treatment and Neuroprotection

  • Yun DaiEmail author
  • Shuang Chen
  • Liang Yi
  • Minhui XuEmail author


Cells traverse the cell cycle through G1 → S → G2 → M phases, and then divide into two daughter cells, which then enter the next cycle or exit to a quiescent G0 phase. This process is tightly controlled by serine–threonine kinases named cyclin-dependent kinases (CDKs). CDKs, as catalytic subunits, become active only in association with their regulatory partner cyclins (e.g., cyclin D–CDK4/CDK6, cyclin E–CDK2, cyclin A–CDK2, cyclin B–CDK1, cyclin C–CDK3). Full activation of the cyclin–CDK holoenzymes requires phosphorylation at particular sites in CDKs. CDK activity is also negatively regulated by direct interaction with CDK inhibitors, which consist of two families, the inhibitor of CDK4 (INK4) family, which specifically inhibit cyclin D-associated kinases, and the kinase inhibitor protein (Cip/Kip) family, which inhibit most CDKs. Dysregulation of these genes (e.g., CDK inhibitors, cyclins, and CDKs themselves) is a common mechanism responsible for out-of-control cell growth, the main characteristic in cancer. Beyond cell cycle regulation, CDKs also play critical roles in gene transcription and neuronal function. In the former case, cyclin T–CDK9 and cyclin C–CDK8 are only involved in transcriptional regulation, whereas cyclin H–CDK7 is involved in regulation of both the cell cycle and transcription. In the latter case, so far CDK5 is the only characterized neuron-specific CDK that appears to function as a double-edged sword dependent on its binding partners (i.e., physiological p35/p39 vs pathological p25). Thus, CDKs are attractive targets for both cancer therapy and neuroprotection, and numerous pharmacological CDK inhibitors have been reported. One major challenge remains whether and how CDK(s) should be inhibited in either of the circumstances. This review summarizes current understanding and recent advances in this field.


Mantle Cell Lymphoma Human Leukemia Cell Mediator Complex Cell Cycle Reentry CDK8 Module 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by two RO1 grants (CA100866 and CA93738), a Multiple Myeloma SPORE award (1 P50 CA142509-01) and its Developmental Research Program subaward (29859/98018093) from the National Cancer Institute, and an award (6181-10) from the Leukemia and Lymphoma Society of America.


  1. Achenbach TV, Muller R, Slater EP (2000) Bcl-2 independence of flavopiridol-induced apoptosis. Mitochondrial depolarization in the absence of cytochrome c release. J Biol Chem 275:32089–32097Google Scholar
  2. Aggarwal BB, Sethi G, Ahn KS, Sandur SK, Pandey MK, Kunnumakkara AB, Sung B, Ichikawa H (2006) Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci 1091:151–169Google Scholar
  3. Akiyama T, Yoshida T, Tsujita T, Shimizu M, Mizukami T, Okabe M, Akinaga S (1997) 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 57:1495–1501PubMedGoogle Scholar
  4. Akoulitchev S, Chuikov S, Reinberg D (2000) TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 407(6800):102–106PubMedCrossRefGoogle Scholar
  5. Almenara J, Rosato R, Grant S (2002) Synergistic induction of mitochondrial damage and apoptosis in human leukemia cells by flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Leukemia 16:1331–1343PubMedCrossRefGoogle Scholar
  6. Alvi AJ, Austen B, Weston VJ, Fegan C, MacCallum D, Gianella-Borradori A, Lane DP, Hubank M, Powell JE, Wei W, Taylor AM, Moss PA, Stankovic T (2005) A novel CDK inhibitor, CYC202 (R-roscovitine), overcomes the defect in p53-dependent apoptosis in B-CLL by down-regulation of genes involved in transcription regulation and survival. Blood 105:4484–4491PubMedCrossRefGoogle Scholar
  7. Arnold A, Papanikolaou A (2005) Cyclin D1 in breast cancer pathogenesis. J Clin Oncol 23:4215–4224PubMedCrossRefGoogle Scholar
  8. Asada A, Saito T, Hisanaga S (2012) Phosphorylation of p35 and p39 by Cdk5 determines the subcellular location of the holokinase in a phosphorylation-site-specific manner. J Cell Sci 125:3421–3429PubMedCrossRefGoogle Scholar
  9. Auerkari EI (2006) Methylation of tumor suppressor genes p16(INK4a), p27(Kip1) and E-cadherin in carcinogenesis. Oral Oncol 42:5–13PubMedCrossRefGoogle Scholar
  10. Bach S, Knockaert M, Reinhardt J, Lozach O, Schmitt S, Baratte B, Koken M, Coburn SP, Tang L, Jiang T, Liang DC, Galons H, Dierick JF, Pinna LA, Meggio F, Totzke F, Schachtele C, Lerman AS, Carnero A, Wan Y, Gray N, Meijer L (2005) Roscovitine targets, protein kinases and pyridoxal kinase. J Biol Chem 280:31208–31219PubMedCrossRefGoogle Scholar
  11. Barboric M, Kohoutek J, Price JP, Blazek D, Price DH, Peterlin BM (2005) Interplay between 7SK snRNA and oppositely charged regions in HEXIM1 direct the inhibition of P-TEFb. EMBO J 24:4291–4303PubMedCrossRefGoogle Scholar
  12. Barette C, Jariel-Encontre I, Piechaczyk M, Piette J (2001) Human cyclin C protein is stabilized by its associated kinase cdk8, independently of its catalytic activity. Oncogene 20:551–562PubMedCrossRefGoogle Scholar
  13. Barriere C, Santamaria D, Cerqueira A, Galan J, Martin A, Ortega S, Malumbres M, Dubus P, Barbacid M (2007) Mice thrive without Cdk4 and Cdk2. Mol Oncol 1:72–83PubMedCrossRefGoogle Scholar
  14. Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3(5):421–429PubMedCrossRefGoogle Scholar
  15. Bartkowiak B, Liu P, Phatnani HP, Fuda NJ, Cooper JJ, Price DH, Adelman K, Lis JT, Greenleaf AL (2010) CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1. Genes Dev 24:2303–2316PubMedCrossRefGoogle Scholar
  16. Bates DJ, Salerni BL, Lowrey CH, Eastman A (2011) Vinblastine sensitizes leukemia cells to cyclin-dependent kinase inhibitors, inducing acute cell cycle phase-independent apoptosis. Cancer Biol Ther 12:314–325PubMedCrossRefGoogle Scholar
  17. Becker EB, Bonni A (2005) Beyond proliferation–cell cycle control of neuronal survival and differentiation in the developing mammalian brain. Semin Cell Dev Biol 16:439–448PubMedCrossRefGoogle Scholar
  18. Benson C, Kaye S, Workman P, Garrett M, Walton M, De BJ (2005) Clinical anticancer drug development: targeting the cyclin-dependent kinases. Br J Cancer 92:7–12PubMedCrossRefGoogle Scholar
  19. Benson C, White J, De BJ, O’Donnell A, Raynaud F, Cruickshank C, McGrath H, Walton M, Workman P, Kaye S, Cassidy J, Gianella-Borradori A, Judson I, Twelves C (2007) A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer 96:29–37PubMedCrossRefGoogle Scholar
  20. Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J Jr (2005) Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 106:296–303PubMedCrossRefGoogle Scholar
  21. Bible KC, Bible RH Jr, Kottke TJ, Svingen PA, Xu K, Pang YP, Hajdu E, Kaufmann SH (2000) Flavopiridol binds to duplex DNA. Cancer Res 60:2419–2428PubMedGoogle Scholar
  22. Blagosklonny MV (2004) Flavopiridol, an inhibitor of transcription: implications, problems and solutions. Cell Cycle 3:1537–1542PubMedCrossRefGoogle Scholar
  23. Blazek D, Kohoutek J, Bartholomeeusen K, Johansen E, Hulinkova P, Luo Z, Cimermancic P, Ule J, Peterlin BM (2011) The cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev 25:2158–2172PubMedCrossRefGoogle Scholar
  24. Brüsselbach S, Nettelbeck DM, Sedlacek HH, Muller R (1998) Cell cycle-independent induction of apoptosis by the anti-tumor drug flavopiridol in endothelial cells. Int J Cancer 77:146–152PubMedCrossRefGoogle Scholar
  25. Burd CJ, Petre CE, Morey LM, Wang Y, Revelo MP, Haiman CA, Lu S, Fenoglio-Preiser CM, Li J, Knudsen ES, Wong J, Knudsen KE (2006) Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation. Proc Natl Acad Sci USA 103:2190–2195PubMedCrossRefGoogle Scholar
  26. Byrd JC, Lin TS, Dalton JT, Wu D, Phelps MA, Fischer B, Moran M, Blum KA, Rovin B, Brooker-McEldowney M, Broering S, Schaaf LJ, Johnson AJ, Lucas DM, Heerema NA, Lozanski G, Young DC, Suarez JR, Colevas AD, Grever MR (2007) Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 109:399–404PubMedCrossRefGoogle Scholar
  27. Cai D, Latham VM Jr, Zhang X, Shapiro GI (2006) Combined depletion of cell cycle and transcriptional cyclin-dependent kinase activities induces apoptosis in cancer cells. Cancer Res 66:9270–9280PubMedCrossRefGoogle Scholar
  28. Callegari AJ, Kelly TJ (2007) Shedding light on the DNA damage checkpoint. Cell Cycle 6(6):660–666PubMedCrossRefGoogle Scholar
  29. Canavese M, Santo L, Raje N (2012) Cyclin dependent kinases in cancer: potential for therapeutic intervention. Cancer Biol Ther 13:451–457PubMedCrossRefGoogle Scholar
  30. Canduri F, Perez PC, Caceres RA, de Azevedo WFJ (2008) CDK9 a potential target for drug development. Med Chem 4:210–218PubMedCrossRefGoogle Scholar
  31. Carlson B, Lahusen T, Singh S, Loaiza-Perez A, Worland PJ, Pestell R, Albanese C, Sausville EA, Senderowicz AM (1999) Down-regulation of cyclin D1 by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol. Cancer Res 59:4634–4641PubMedGoogle Scholar
  32. Carrere N, Belaud-Rotureau MA, Dubus P, Parrens M, de MA, Merlio JP (2005) The relative levels of cyclin D1a and D1b alternative transcripts in mantle cell lymphoma may depend more on sample origin than on CCND1 polymorphism. Haematologica 90:854–885Google Scholar
  33. Cartee L, Wang Z, Decker RH, Chellappan SP, Fusaro G, Hirsch KG, Sankala HM, Dent P, Grant S (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 61:2583–2591PubMedGoogle Scholar
  34. Cartee L, Smith R, Dai Y, Rahmani M, Rosato R, Almenara J, Dent P, Grant S (2002) Synergistic induction of apoptosis in human myeloid leukemia cells by phorbol 12-myristate 13-acetate and flavopiridol proceeds via activation of both the intrinsic and tumor necrosis factor-mediated extrinsic cell death pathways. Mol Pharmacol 61:1313–1321PubMedCrossRefGoogle Scholar
  35. Castedo M, Perfettini JL, Roumier T, Kroemer G (2002) Cyclin-dependent kinase-1: linking apoptosis to cell cycle and mitotic catastrophe. Cell Death Differ 9:1287–1293PubMedCrossRefGoogle Scholar
  36. Chakravarti A, DeSilvio M, Zhang M, Grignon D, Rosenthal S, Asbell SO, Hanks G, Sandler HM, Khor LY, Pollack A, Shipley W (2007) Prognostic value of p16 in locally advanced prostate cancer: a study based on Radiation Therapy Oncology Group Protocol 9202. J Clin Oncol 25:3082–3089PubMedCrossRefGoogle Scholar
  37. Chao SH, Fujinaga K, Marion JE, Taube R, Sausville EA, Senderowicz AM, Peterlin BM, Price DH (2000) Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J Biol Chem 275:28345–28348PubMedCrossRefGoogle Scholar
  38. Chao SH, Price DH (2001) Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem 276:31793–31799PubMedCrossRefGoogle Scholar
  39. Chen HH, Wang YC, Fann MJ (2006) Identification and characterization of the CDK12/cyclin L1 complex involved in alternative splicing regulation. Mol Cell Biol 26:2736–2745PubMedCrossRefGoogle Scholar
  40. Chen HH, Wong YH, Geneviere AM, Fann MJ (2007a) CDK13/CDC2L5 interacts with L-type cyclins and regulates alternative splicing. Biochem Biophys Res Commun 354:735–740PubMedCrossRefGoogle Scholar
  41. Chen S, Dai Y, Harada H, Dent P, Grant S (2007b) Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res 67:782–791PubMedCrossRefGoogle Scholar
  42. Chen S, Dai Y, Pei XY, Myers J, Wang L, Kramer LB, Garnett M, Schwartz DM, Su F, Simmons GL, Richey JD, Larsen DG, Dent P, Orlowski RZ, Grant S (2012) CDK inhibitors upregulate BH3-only proteins to sensitize human myeloma cells to BH3 mimetic therapies. Cancer Res 72:4225–4237PubMedCrossRefGoogle Scholar
  43. Cheng B, Price DH (2007) Properties of RNA polymerase II elongation complexes before and after the P-TEFb-mediated transition into productive elongation. J Biol Chem 282:21901–21912PubMedCrossRefGoogle Scholar
  44. Chen-Kiang S (2003) Cell-cycle control of plasma cell differentiation and tumorigenesis. Immunol Rev 194:39–47PubMedCrossRefGoogle Scholar
  45. Cheung ZH, Ip NY (2004) Cdk5: mediator of neuronal death and survival. Neurosci Lett 361:47–51PubMedCrossRefGoogle Scholar
  46. Cheung ZH, Ip NY (2007) The roles of cyclin-dependent kinase 5 in dendrite and synapse development. Biotechnol J 2:949–957PubMedCrossRefGoogle Scholar
  47. Cheung ZH, Fu AK, Ip NY (2006) Synaptic roles of Cdk5: implications in higher cognitive functions and neurodegenerative diseases. Neuron 50:13–18PubMedCrossRefGoogle Scholar
  48. Cheung ZH, Chin WH, Chen Y, Ng YP, Ip NY (2007) Cdk5 is involved in BDNF-stimulated dendritic growth in hippocampal neurons. PLoS Biol 5:e63PubMedCrossRefGoogle Scholar
  49. Cheung ZH, Gong K, Ip NY (2008) Cyclin-dependent kinase 5 supports neuronal survival through phosphorylation of Bcl-2. J Neurosci 28:4872–4877PubMedCrossRefGoogle Scholar
  50. Chim CS, Fung TK, Liang R (2003) Disruption of INK4/CDK/Rb cell cycle pathway by gene hypermethylation in multiple myeloma and MGUS. Leukemia 17:2533–2535PubMedCrossRefGoogle Scholar
  51. Cicenas J, Valius M (2011) The CDK inhibitors in cancer research and therapy. J Cancer Res Clin Oncol 137:1409–1418PubMedCrossRefGoogle Scholar
  52. Ciemerych MA, Yu Q, Szczepanska K, Sicinski P (2008) CDK4 activity in mouse embryos expressing a single D-type cyclin. Int J Dev Biol 52:299–305PubMedCrossRefGoogle Scholar
  53. Colevas D, Blaylock B, Gravell A (2002) Clinical trials referral resource. Flavopiridol. Oncology (Williston Park) 16:1204–1212, 1214Google Scholar
  54. Coley HM, Shotton CF, Kokkinos MI, Thomas H (2007a) The effects of the CDK inhibitor seliciclib alone or in combination with cisplatin in human uterine sarcoma cell lines. Gynecol Oncol 105:462–469PubMedCrossRefGoogle Scholar
  55. Coley HM, Shotton CF, Thomas H (2007b) Seliciclib (CYC202; r-roscovitine) in combination with cytotoxic agents in human uterine sarcoma cell lines. Anticancer Res 27:273–278Google Scholar
  56. Coqueret O (2002) Linking cyclins to transcriptional control. Gene 299:35–55PubMedCrossRefGoogle Scholar
  57. Coudreuse D, Nurse P (2010) Driving the cell cycle with a minimal CDK control network. Nature 468:1074–1079PubMedCrossRefGoogle Scholar
  58. Croxton R, Ma Y, Song L, Haura EB, Cress WD (2002) Direct repression of the Mcl-1 promoter by E2F1. Oncogene 21:1359–1369PubMedCrossRefGoogle Scholar
  59. Cruz JC, Tseng HC, Goldman JA, Shih H, Tsai LH (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40(3):471–483PubMedCrossRefGoogle Scholar
  60. Cruz JC, Tsai LH (2004a) A Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease. Curr Opin Neurobiol 14:390–394PubMedCrossRefGoogle Scholar
  61. Cruz JC, Tsai LH (2004b) Cdk5 deregulation in the pathogenesis of Alzheimer’s disease. Trends Mol Med 10:452–458PubMedCrossRefGoogle Scholar
  62. Cruz JC, Kim D, Moy LY, Dobbin MM, Sun X, Bronson RT, Tsai LH (2006) p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo. J Neurosci 26:10536–10541PubMedCrossRefGoogle Scholar
  63. Dai Y, Grant S (2003) Cyclin-dependent kinase inhibitors. Curr Opin Pharmacol 3:362–370PubMedCrossRefGoogle Scholar
  64. Dai Y, Grant S (2004) Small molecule inhibitors targeting cyclin-dependent kinases as anticancer agents. Curr Oncol Rep 6:123–130PubMedCrossRefGoogle Scholar
  65. Dai Y, Grant S (2006) CDK inhibitor targets: a hit or miss proposition? Cyclin-dependent kinase inhibitors kill tumor cells by downregulation of anti-apoptotic proteins. Cancer Biol Ther 5:171–173PubMedCrossRefGoogle Scholar
  66. Dai Y, Grant S (2010a) New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res 16:376–383PubMedCrossRefGoogle Scholar
  67. Dai Y, Grant S (2010b) Targeting Chk1 in the replicative stress response. Cell Cycle 9:1025PubMedCrossRefGoogle Scholar
  68. Dai Y, Grant S (2011) Methods to study cancer therapeutic drugs that target cell cycle checkpoints. Methods Mol Biol 782:257–304PubMedCrossRefGoogle Scholar
  69. Dai Y, Yu C, Singh V, Tang L, Wang Z, McInistry R, Dent P, Grant S (2001) Pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase/MAPK cascade interact synergistically with UCN-01 to induce mitochondrial dysfunction and apoptosis in human leukemia cells. Cancer Res 61:5106–5115PubMedGoogle Scholar
  70. Dai Y, Dent P, Grant S (2002a) Induction of apoptosis in human leukemia cells by the CDK1 inhibitor CGP74514A. Cell Cycle 1:143–152PubMedGoogle Scholar
  71. Dai Y, Landowski TH, Rosen ST, Dent P, Grant S (2002b) Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6-independent mechanism. Blood 100:3333–3343PubMedCrossRefGoogle Scholar
  72. Dai Y, Dent P, Grant S (2003a) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes mitochondrial dysfunction and apoptosis induced by 7-hydroxystaurosporine and mitogen-activated protein kinase kinase inhibitors in human leukemia cells that ectopically express Bcl-2 and Bcl-xL. Mol Pharmacol 64:1402–1409PubMedCrossRefGoogle Scholar
  73. Dai Y, Rahmani M, Grant S (2003b) An intact NF-kappaB pathway is required for histone deacetylase inhibitor-induced G1 arrest and maturation in U937 human myeloid leukemia cells. Cell Cycle 2:467–472PubMedCrossRefGoogle Scholar
  74. Dai Y, Rahmani M, Grant S (2003c) Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-kappaB-dependent process. Oncogene 22:7108–7122PubMedCrossRefGoogle Scholar
  75. Dai Y, Pei XY, Rahmani M, Conrad DH, Dent P, Grant S (2004a) Interruption of the NF-kappaB pathway by Bay 11–7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells. Blood 103:2761–2770PubMedCrossRefGoogle Scholar
  76. Dai Y, Rahmani M, Pei XY, Dent P, Grant S (2004b) Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. Blood 104:509–518PubMedCrossRefGoogle Scholar
  77. Dai Y, Rahmani M, Dent P, Grant S (2005a) Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol Cell Biol 25:5429–5444PubMedCrossRefGoogle Scholar
  78. Dai Y, Rahmani M, Pei XY, Khanna P, Han SI, Mitchell C, Dent P, Grant S (2005b) Farnesyltransferase inhibitors interact synergistically with the Chk1 inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK. Blood 105:1706–1716PubMedCrossRefGoogle Scholar
  79. Dai Y, Hamm TE, Dent P, Grant S (2006) Cyclin D1 overexpression increases the susceptibility of human U266 myeloma cells to CDK inhibitors through a process involving p130-, p107- and E2F-dependent S phase entry. Cell Cycle 5:437–446PubMedCrossRefGoogle Scholar
  80. Dai Y, Khanna P, Chen S, Pei XY, Dent P, Grant S (2007) Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human leukemia and myeloma cells by disrupting Ras farnesylation and activation. Blood 109:4415–4423PubMedCrossRefGoogle Scholar
  81. Dai Y, Chen S, Kramer LB, Funk VL, Dent P, Grant S (2008a) Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells. Clin Cancer Res 14:549–558PubMedCrossRefGoogle Scholar
  82. Dai Y, Chen S, Pei XY, Almenara JA, Kramer LB, Venditti CA, Dent P, Grant S (2008b) Interruption of the Ras/MEK/ERK signaling cascade enhances Chk1 inhibitor-induced DNA damage in vitro and in vivo in human multiple myeloma cells. Blood 112:2439–2449PubMedCrossRefGoogle Scholar
  83. Dai Y, Chen S, Venditti CA, Pei XY, Nguyen TK, Dent P, Grant S (2008c) Vorinostat synergistically potentiates MK-0457 lethality in chronic myelogenous leukemia cells sensitive and resistant to imatinib mesylate. Blood 112:793–804PubMedCrossRefGoogle Scholar
  84. Dai Y, Chen S, Shah R, Pei XY, Wang L, Almenara JA, Kramer LB, Dent P, Grant S (2011a) Disruption of Src function potentiates Chk1-inhibitor-induced apoptosis in human multiple myeloma cells in vitro and in vivo. Blood 117:1947–1957PubMedCrossRefGoogle Scholar
  85. Dai Y, Chen S, Wang L, Pei XY, Funk VL, Kramer LB, Dent P, Grant S (2011b) Disruption of IkappaB kinase (IKK)-mediated RelA serine 536 phosphorylation sensitizes human multiple myeloma cells to histone deacetylase (HDAC) inhibitors. J Biol Chem 286:34036–34050PubMedCrossRefGoogle Scholar
  86. Dai Y, Chen S, Wang L, Pei XY, Kramer LB, Dent P, Grant S (2011c) Bortezomib interacts synergistically with belinostat in human acute myeloid leukaemia and acute lymphoblastic leukaemia cells in association with perturbations in NF-kappaB and Bim. Br J Haematol 153(2):222–235PubMedCrossRefGoogle Scholar
  87. Davies TG, Bentley J, Arris CE, Boyle FT, Curtin NJ, Endicott JA, Gibson AE, Golding BT, Griffin RJ, Hardcastle IR, Jewsbury P, Johnson LN, Mesguiche V, Newell DR, Noble ME, Tucker JA, Wang L, Whitfield HJ (2002) Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor. Nat Struct Biol 9:745–749PubMedCrossRefGoogle Scholar
  88. de Azevedo WFJ, Canduri F, da Silveira NJ (2002) Structural basis for inhibition of cyclin-dependent kinase 9 by flavopiridol. Biochem Biophys Res Commun 293:566–571PubMedCrossRefGoogle Scholar
  89. Decker RH, Dai Y, Grant S (2001) The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in human leukemia cells (U937) through the mitochondrial rather than the receptor-mediated pathway. Cell Death Differ 8:715–724PubMedCrossRefGoogle Scholar
  90. Decker RH, Wang S, Dai Y, Dent P, Grant S (2002) Loss of the Bcl-2 phosphorylation loop domain is required to protect human myeloid leukemia cells from flavopiridol-mediated mitochondrial damage and apoptosis. Cancer Biol Ther 1:136–144PubMedGoogle Scholar
  91. Dees EC, Baker SD, O’Reilly S, Rudek MA, Davidson SB, Aylesworth C, Elza-Brown K, Carducci MA, Donehower RC (2005) A phase I and pharmacokinetic study of short infusions of UCN-01 in patients with refractory solid tumors. Clin Cancer Res 11:664–671PubMedGoogle Scholar
  92. Delmer A, Ajchenbaum-Cymbalista F, Tang R, Ramond S, Faussat AM, Marie JP, Zittoun R (1995) Overexpression of cyclin D2 in chronic B-cell malignancies. Blood 85:2870–2876PubMedGoogle Scholar
  93. Dent P, Tang Y, Yacoub A, Dai Y, Fisher PB, Grant S (2011) CHK1 inhibitors in combination chemotherapy: thinking beyond the cell cycle. Mol Interv 11:133–140PubMedCrossRefGoogle Scholar
  94. Deshpande A, Sicinski P, Hinds PW (2005) Cyclins and cdks in development and cancer: a perspective. Oncogene 24:2909–2915PubMedCrossRefGoogle Scholar
  95. Di Giovanni S, Movsesyan V, Ahmed F, Cernak I, Schinelli S, Stoica B, Faden AI (2005) Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury. Proc Natl Acad Sci USA 102:8333–8338PubMedCrossRefGoogle Scholar
  96. Dib A, Peterson TR, Raducha-Grace L, Zingone A, Zhan F, Hanamura I, Barlogie B, Shaughnessy J Jr, Kuehl WM (2006) Paradoxical expression of INK4c in proliferative multiple myeloma tumors: bi-allelic deletion vs increased expression. Cell Div 1:23Google Scholar
  97. Diehl JA, Zindy F, Sherr CJ (1997) Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes Dev 11:957–972PubMedCrossRefGoogle Scholar
  98. Dong Y, Sui L, Tai Y, Sugimoto K, Tokuda M (2001) The overexpression of cyclin-dependent kinase (CDK) 2 in laryngeal squamous cell carcinomas. Anticancer Res 21:103–108Google Scholar
  99. Drexler HG (1998) Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells. Leukemia 12:845–859PubMedCrossRefGoogle Scholar
  100. Echalier A, Endicott JA, Noble ME (2010) Recent developments in cyclin-dependent kinase biochemical and structural studies. Biochim Biophys Acta 1804:511–519Google Scholar
  101. Egloff S, Van HE, Kiss T (2006) Regulation of polymerase II transcription by 7SK snRNA: two distinct RNA elements direct P-TEFb and HEXIM1 binding. Mol Cell Biol 26:630–642PubMedCrossRefGoogle Scholar
  102. Ely S, Di LM, Niesvizky R, Baughn LB, Cho HJ, Hatada EN, Knowles DM, Lane J, Chen-Kiang S (2005) Mutually exclusive cyclin-dependent kinase 4/cyclin D1 and cyclin-dependent kinase 6/cyclin D2 pairing inactivates retinoblastoma protein and promotes cell cycle dysregulation in multiple myeloma. Cancer Res 65:11345–11353PubMedCrossRefGoogle Scholar
  103. Evens AM, Gartenhaus RB (2003) Molecular etiology of mature T-cell non-Hodgkin’s lymphomas. Front Biosci 8:d156–d175PubMedCrossRefGoogle Scholar
  104. Ezhevsky SA, Ho A, Becker-Hapak M, Davis PK, Dowdy SF (2001) Differential regulation of retinoblastoma tumor suppressor protein by G(1) cyclin-dependent kinase complexes in vivo. Mol Cell Biol 21:4773–4784PubMedCrossRefGoogle Scholar
  105. Feldmann G, Mishra A, Bisht S, Karikari C, Garrido-Laguna I, Rasheed Z, Ottenhof NA, Dadon T, Alvarez H, Fendrich V, Rajeshkumar NV, Matsui W, Brossart P, Hidalgo M, Bannerji R, Maitra A, Nelkin BD (2011) Cyclin-dependent kinase inhibitor dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models. Cancer Biol Ther 12:598–609PubMedCrossRefGoogle Scholar
  106. Firestein R, Bass AJ, Kim SY, Dunn IF, Silver SJ, Guney I, Freed E, Ligon AH, Vena N, Ogino S, Chheda MG, Tamayo P, Finn S, Shrestha Y, Boehm JS, Jain S, Bojarski E, Mermel C, Barretina J, Chan JA, Baselga J, Tabernero J, Root DE, Fuchs CS, Loda M, Shivdasani RA, Meyerson M, Hahn WC (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature 455:547–551PubMedCrossRefGoogle Scholar
  107. Fry DW, Bedford DC, Harvey PH, Fritsch A, Keller PR, Wu Z, Dobrusin E, Leopold WR, Fattaey A, Garrett MD (2001) Cell cycle and biochemical effects of PD 0183812. A potent inhibitor of the cyclin D-dependent kinases CDK4 and CDK6. J Biol Chem 276:16617–16623Google Scholar
  108. Fu TJ, Peng J, Lee G, Price DH, Flores O (1999) Cyclin K functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription. J Biol Chem 274:34527–34530PubMedCrossRefGoogle Scholar
  109. Fu M, Wang C, Li Z, Sakamaki T, Pestell RG (2004) Minireview: cyclin D1: normal and abnormal functions. Endocrinology 145:5439–5447PubMedCrossRefGoogle Scholar
  110. Fu M, Rao M, Bouras T, Wang C, Wu K, Zhang X, Li Z, Yao TP, Pestell RG (2005) Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment. J Biol Chem 280:16934–16941PubMedCrossRefGoogle Scholar
  111. Fu W, Ma L, Chu B, Wang X, Bui MM, Gemmer J, Altiok S, Pledger WJ (2011) The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells. Mol Cancer Ther 10:1018–1027PubMedCrossRefGoogle Scholar
  112. Fujinaga K, Barboric M, Li Q, Luo Z, Price DH, Peterlin BM (2012) PKC phosphorylates HEXIM1 and regulates P-TEFb activity. Nucleic Acids Res 40:9160–9170PubMedCrossRefGoogle Scholar
  113. Fukasawa R, Tsutsui T, Hirose Y, Tanaka A, Ohkuma Y (2012) Mediator CDK subunits are platforms for interactions with various chromatin regulatory complexes. J Biochem 152:241–249PubMedCrossRefGoogle Scholar
  114. Fulda S, Debatin KM (2006) Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25:4798–4811PubMedCrossRefGoogle Scholar
  115. Fuse E, Kuwabara T, Sparreboom A, Sausville EA, Figg WD (2005) Review of UCN-01 development: a lesson in the importance of clinical pharmacology. J Clin Pharmacol 45:394–403PubMedCrossRefGoogle Scholar
  116. Galbraith MD, Donner AJ, Espinosa JM (2010) CDK8: a positive regulator of transcription. Transcription 1:4–12PubMedCrossRefGoogle Scholar
  117. Gallorini M, Cataldi A, di Giacomo V (2012) Cyclin-dependent kinase modulators and cancer therapy. Biodrugs 26:377–391Google Scholar
  118. Galm O, Wilop S, Reichelt J, Jost E, Gehbauer G, Herman JG, Osieka R (2004) DNA methylation changes in multiple myeloma. Leukemia 18:1687–1692PubMedCrossRefGoogle Scholar
  119. Ganuza M, Saiz-Ladera C, Canamero M, Gomez G, Schneider R, Blasco MA, Pisano D, Paramio JM, Santamaria D, Barbacid M (2012) Genetic inactivation of Cdk7 leads to cell cycle arrest and induces premature aging due to adult stem cell exhaustion. EMBO J 31:2498–2510PubMedCrossRefGoogle Scholar
  120. Gao N, Dai Y, Rahmani M, Dent P, Grant S (2004) Contribution of disruption of the nuclear factor-kappaB pathway to induction of apoptosis in human leukemia cells by histone deacetylase inhibitors and flavopiridol. Mol Pharmacol 66:956–963PubMedCrossRefGoogle Scholar
  121. Garriga J, Grana X (2004) Cellular control of gene expression by T-type cyclin/CDK9 complexes. Gene 337:15–23PubMedCrossRefGoogle Scholar
  122. Garriga J, Xie H, Obradovic Z, Grana X (2010) Selective control of gene expression by CDK9 in human cells. J Cell Physiol 222:200–208PubMedCrossRefGoogle Scholar
  123. Geng Y, Yu Q, Sicinska E, Das M, Schneider JE, Bhattacharya S, Rideout WM, Bronson RT, Gardner H, Sicinski P (2003) Cyclin E ablation in the mouse. Cell 114:431–443PubMedCrossRefGoogle Scholar
  124. Glover-Cutter K, Larochelle S, Erickson B, Zhang C, Shokat K, Fisher RP, Bentley DL (2009) TFIIH-associated Cdk7 kinase functions in phosphorylation of C-terminal domain Ser7 residues, promoter-proximal pausing, and termination by RNA polymerase II. Mol Cell Biol 29:5455–5464PubMedCrossRefGoogle Scholar
  125. Gottifredi V, Prives C (2005) The S phase checkpoint: when the crowd meets at the fork. Semin Cell Dev Biol 16:355–368PubMedCrossRefGoogle Scholar
  126. Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629PubMedCrossRefGoogle Scholar
  127. Greene LA, Liu DX, Troy CM, Biswas SC (2007) Cell cycle molecules define a pathway required for neuron death in development and disease. Biochim Biophys Acta 1772:392–401PubMedCrossRefGoogle Scholar
  128. Hahn M, Li W, Yu C, Rahmani M, Dent P, Grant S (2005) Rapamycin and UCN-01 synergistically induce apoptosis in human leukemia cells through a process that is regulated by the Raf-1/MEK/ERK, Akt, and JNK signal transduction pathways. Mol Cancer Ther 4:457–470PubMedGoogle Scholar
  129. Hahntow IN, Schneller F, Oelsner M, Weick K, Ringshausen I, Fend F, Peschel C, Decker T (2004) Cyclin-dependent kinase inhibitor roscovitine induces apoptosis in chronic lymphocytic leukemia cells. Leukemia 18:747–755PubMedCrossRefGoogle Scholar
  130. Hamed H, Hawkins W, Mitchell C, Gilfor D, Zhang G, Pei XY, Dai Y, Hagan MP, Roberts JD, Yacoub A, Grant S, Dent P (2008) Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell death in vitro and in vivo. Mol Cancer Ther 7:616–629PubMedCrossRefGoogle Scholar
  131. Hardcastle IR, Golding BT, Griffin RJ (2002) Designing inhibitors of cyclin-dependent kinases. Annu Rev Pharmacol Toxicol 42:325–348PubMedCrossRefGoogle Scholar
  132. Harrison JC, Haber JE (2006) Surviving the breakup: the DNA damage checkpoint. Annu Rev Genet 40:209–235PubMedCrossRefGoogle Scholar
  133. Harvey S, Decker R, Dai Y, Schaefer G, Tang L, Kramer L, Dent P, Grant S (2001) Interactions between 2-fluoroadenine 9-beta-D-arabinofuranoside and the kinase inhibitor UCN-01 in human leukemia and lymphoma cells. Clin Cancer Res 7:320–330PubMedGoogle Scholar
  134. Hawkins W, Mitchell C, McKinstry R, Gilfor D, Starkey J, Dai Y, Dawson K, Ramakrishnan V, Roberts JD, Yacoub A, Grant S, Dent P (2005) Transient exposure of mammary tumors to PD184352 and UCN-01 causes tumor cell death in vivo and prolonged suppression of tumor regrowth. Cancer Biol Ther 4:1275–1284PubMedCrossRefGoogle Scholar
  135. Heffernan TP, Simpson DA, Frank AR, Heinloth AN, Paules RS, Cordeiro-Stone M, Kaufmann WK (2002) An ATR- and Chk1-dependent S checkpoint inhibits replicon initiation following UVC-induced DNA damage. Mol Cell Biol 22:8552–8561PubMedCrossRefGoogle Scholar
  136. Hindley C, Philpott A (2012) Co-ordination of cell cycle and differentiation in the developing nervous system. Biochem J 444:375–382PubMedCrossRefGoogle Scholar
  137. Hisanaga S, Saito T (2003) The regulation of cyclin-dependent kinase 5 activity through the metabolism of p35 or p39 Cdk5 activator. Neurosignals 12:221–229PubMedCrossRefGoogle Scholar
  138. Hisanaga S, Endo R (2010) Regulation and role of cyclin-dependent kinase activity in neuronal survival and death. J Neurochem 115:1309–1321PubMedCrossRefGoogle Scholar
  139. Hisanaga S, Asada A (2012) Cdk5-induced neuronal cell death: the activation of the conventional Rb-E2F G 1 pathway in post-mitotic neurons. Cell Cycle 11:2049PubMedCrossRefGoogle Scholar
  140. Hoeppner S, Baumli S, Cramer P (2005) Structure of the mediator subunit cyclin C and its implications for CDK8 function. J Mol Biol 350:833–842PubMedCrossRefGoogle Scholar
  141. Hofmann J (2004) Protein kinase C isozymes as potential targets for anticancer therapy. Curr Cancer Drug Targets 4:125–146PubMedCrossRefGoogle Scholar
  142. Hofmann F, Livingston DM (1996) Differential effects of cdk2 and cdk3 on the control of pRb and E2F function during G1 exit. Genes Dev 10:851–861PubMedCrossRefGoogle Scholar
  143. Holkova B, Perkins EB, Ramakrishnan V, Tombes MB, Shrader E, Talreja N, Wellons MD, Hogan KT, Roodman GD, Coppola D, Kang L, Dawson J, Stuart RK, Peer C, Figg WD Sr, Kolla S, Doyle A, Wright J, Sullivan DM, Roberts JD, Grant S (2011) Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms. Clin Cancer Res 17:3388–3397PubMedCrossRefGoogle Scholar
  144. Honma T, Hayashi K, Aoyama T, Hashimoto N, Machida T, Fukasawa K, Iwama T, Ikeura C, Ikuta M, Suzuki-Takahashi I, Iwasawa Y, Hayama T, Nishimura S, Morishima H (2001) Structure-based generation of a new class of potent Cdk4 inhibitors: new de novo design strategy and library design. J Med Chem 44:4615–4627PubMedCrossRefGoogle Scholar
  145. Honma N, Asada A, Takeshita S, Enomoto M, Yamakawa E, Tsutsumi K, Saito T, Satoh T, Itoh H, Kaziro Y, Kishimoto T, Hisanaga S (2003) Apoptosis-associated tyrosine kinase is a Cdk5 activator p35 binding protein. Biochem Biophys Res Commun 310:398–404PubMedCrossRefGoogle Scholar
  146. Horiuchi D, Huskey NE, Kusdra L, Wohlbold L, Merrick KA, Zhang C, Creasman KJ, Shokat KM, Fisher RP, Goga A (2012) Chemical-genetic analysis of cyclin dependent kinase 2 function reveals an important role in cellular transformation by multiple oncogenic pathways. Proc Natl Acad Sci USA 109:E1019–E1027PubMedCrossRefGoogle Scholar
  147. Hosokawa Y, Arnold A (1998) Mechanism of cyclin D1 (CCND1, PRAD1) overexpression in human cancer cells: analysis of allele-specific expression. Genes Chromosomes Cancer 22:66–71PubMedCrossRefGoogle Scholar
  148. Hu X, Moscinski LC (2011) Cdc2: a monopotent or pluripotent CDK? Cell Prolif 44:205–211PubMedCrossRefGoogle Scholar
  149. Hu D, Mayeda A, Trembley JH, Lahti JM, Kidd VJ (2003) CDK11 complexes promote pre-mRNA splicing. J Biol Chem 278:8623–8629PubMedCrossRefGoogle Scholar
  150. Hulit J, Bash T, Fu M, Galbiati F, Albanese C, Sage DR, Schlegel A, Zhurinsky J, Shtutman M, Ben-Ze’ev A, Lisanti MP, Pestell RG (2000) The cyclin D1 gene is transcriptionally repressed by caveolin-1. J Biol Chem 275:21203–21209PubMedCrossRefGoogle Scholar
  151. Husseman JW, Nochlin D, Vincent I (2000) Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases. Neurobiol Aging 21:815–828PubMedCrossRefGoogle Scholar
  152. Ikuta M, Kamata K, Fukasawa K, Honma T, Machida T, Hirai H, Suzuki-Takahashi I, Hayama T, Nishimura S (2001) Crystallographic approach to identification of cyclin-dependent kinase 4 (CDK4)-specific inhibitors by using CDK4 mimic CDK2 protein. J Biol Chem 276:27548–27554PubMedCrossRefGoogle Scholar
  153. Iorns E, Turner NC, Elliott R, Syed N, Garrone O, Gasco M, Tutt AN, Crook T, Lord CJ, Ashworth A (2008) Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer. Cancer Cell 13:91–104PubMedCrossRefGoogle Scholar
  154. Jirmanova L, Afanassieff M, Gobert-Gosse S, Markossian S, Savatier P (2002) Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells. Oncogene 21:5515–5528PubMedCrossRefGoogle Scholar
  155. Johnson LN, De ME, Brown NR, Song H, Barford D, Endicott JA, Noble ME (2002) Structural studies with inhibitors of the cell cycle regulatory kinase cyclin-dependent protein kinase 2. Pharmacol Ther 93:113–124PubMedCrossRefGoogle Scholar
  156. Johnson AJ, Yeh YY, Smith LL, Wagner AJ, Hessler J, Gupta S, Flynn J, Jones J, Zhang X, Bannerji R, Grever MR, Byrd JC (2012) The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells. LeukemiaGoogle Scholar
  157. Kaiser A, Nishi K, Gorin FA, Walsh DA, Bradbury EM, Schnier JB (2001) The cyclin-dependent kinase (CDK) inhibitor flavopiridol inhibits glycogen phosphorylase. Arch Biochem Biophys 386:179–187PubMedCrossRefGoogle Scholar
  158. Kamei H, Saito T, Ozawa M, Fujita Y, Asada A, Bibb JA, Saido TC, Sorimachi H, Hisanaga S (2007) Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation. J Biol Chem 282:1687–1694PubMedCrossRefGoogle Scholar
  159. Kapoor A, Goldberg MS, Cumberland LK, Ratnakumar K, Segura MF, Emanuel PO, Menendez S, Vardabasso C, Leroy G, Vidal CI, Polsky D, Osman I, Garcia BA, Hernando E, Bernstein E (2010) The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature 468:1105–1109PubMedCrossRefGoogle Scholar
  160. Karlsson-Rosenthal C, Millar JB (2006) Cdc25: mechanisms of checkpoint inhibition and recovery. Trends Cell Biol 16:285–292PubMedCrossRefGoogle Scholar
  161. Karp JE, Passaniti A, Gojo I, Kaufmann S, Bible K, Garimella TS, Greer J, Briel J, Smith BD, Gore SD, Tidwell ML, Ross DD, Wright JJ, Colevas AD, Bauer KS (2005) Phase I and pharmacokinetic study of flavopiridol followed by 1-beta-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias. Clin Cancer Res 11:8403–8412PubMedCrossRefGoogle Scholar
  162. Kasten M, Giordano A (2001) Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity. Oncogene 20:1832–1838PubMedCrossRefGoogle Scholar
  163. Kato H, Takahashi A, Itoyama Y (2003) Cell cycle protein expression in proliferating microglia and astrocytes following transient global cerebral ischemia in the rat. Brain Res Bull 60:215–221PubMedCrossRefGoogle Scholar
  164. Kawabe T (2004) G2 checkpoint abrogators as anticancer drugs. Mol Cancer Ther 3:513–519PubMedGoogle Scholar
  165. Kim DM, Koo SY, Jeon K, Kim MH, Lee J, Hong CY, Jeong S (2003) Rapid induction of apoptosis by combination of flavopiridol and tumor necrosis factor (TNF)-alpha or TNF-related apoptosis-inducing ligand in human cancer cell lines. Cancer Res 63:621–626PubMedGoogle Scholar
  166. Kitada S, Zapata JM, Andreeff M, Reed JC (2000) Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood 96:393–397PubMedGoogle Scholar
  167. Knockaert M, Greengard P, Meijer L (2002) Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci 23:417–425PubMedCrossRefGoogle Scholar
  168. Knudsen KE, Diehl JA, Haiman CA, Knudsen ES (2006) Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene 25:1620–1628PubMedCrossRefGoogle Scholar
  169. Koguchi K, Nakatsuji Y, Okuno T, Sawada M, Sakoda S (2003) Microglial cell cycle-associated proteins control microglial proliferation in vivo and in vitro and are regulated by GM-CSF and density-dependent inhibition. J Neurosci Res 74:898–905PubMedCrossRefGoogle Scholar
  170. Kohn EA, Ruth ND, Brown MK, Livingstone M, Eastman A (2002) Abrogation of the S phase DNA damage checkpoint results in S phase progression or premature mitosis depending on the concentration of 7-hydroxystaurosporine and the kinetics of Cdc25C activation. J Biol Chem 277:26553–26564PubMedCrossRefGoogle Scholar
  171. Kohno T, Yokota J (2006) Molecular processes of chromosome 9p21 deletions causing inactivation of the p16 tumor suppressor gene in human cancer: deduction from structural analysis of breakpoints for deletions. DNA Repair (Amst) 5:1273–1281CrossRefGoogle Scholar
  172. Kohoutek J, Blazek D (2012) Cyclin K goes with Cdk12 and Cdk13. Cell Div 7:12 Google Scholar
  173. Kohzato N, Dong Y, Sui L, Masaki T, Nagahata S, Nishioka M, Konishi R, Tokuda M (2001) Overexpression of cyclin E and cyclin-dependent kinase 2 is correlated with development of hepatocellular carcinomas. Hepatol Res 21:27–39PubMedCrossRefGoogle Scholar
  174. Komander D, Kular GS, Bain J, Elliott M, Alessi DR, van Aalten DM (2003) Structural basis for UCN-01 (7-hydroxystaurosporine) specificity and PDK1 (3-phosphoinositide-dependent protein kinase-1) inhibition. Biochem J 375:255–262PubMedCrossRefGoogle Scholar
  175. Konishi Y, Lehtinen M, Donovan N, Bonni A (2002) Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Mol Cell 9:1005–1016PubMedCrossRefGoogle Scholar
  176. Kouroukis CT, Belch A, Crump M, Eisenhauer E, Gascoyne RD, Meyer R, Lohmann R, Lopez P, Powers J, Turner R, Connors JM (2003) Flavopiridol in untreated or relapsed mantle-cell lymphoma: results of a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21:1740–1745PubMedCrossRefGoogle Scholar
  177. Kozar K, Ciemerych MA, Rebel VI, Shigematsu H, Zagozdzon A, Sicinska E, Geng Y, Yu Q, Bhattacharya S, Bronson RT, Akashi K, Sicinski P (2004) Mouse development and cell proliferation in the absence of D-cyclins. Cell 118:477–491PubMedCrossRefGoogle Scholar
  178. Krieger S, Gauduchon J, Roussel M, Troussard X, Sola B (2006) Relevance of cyclin D1b expression and CCND1 polymorphism in the pathogenesis of multiple myeloma and mantle cell lymphoma. BMC Cancer 6:238Google Scholar
  179. Krueger BJ, Jeronimo C, Roy BB, Bouchard A, Barrandon C, Byers SA, Searcey CE, Cooper JJ, Bensaude O, Cohen EA, Coulombe B, Price DH (2008) LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated. Nucleic Acids Res 36:2219–2229PubMedCrossRefGoogle Scholar
  180. Krueger BJ, Varzavand K, Cooper JJ, Price DH (2010) The mechanism of release of P-TEFb and HEXIM1 from the 7SK snRNP by viral and cellular activators includes a conformational change in 7SK. PLoS One 5:e12335PubMedCrossRefGoogle Scholar
  181. Kulkarni MS, Daggett JL, Bender TP, Kuehl WM, Bergsagel PL, Williams ME (2002) 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 16:127–134PubMedCrossRefGoogle Scholar
  182. Lacrima K, Valentini A, Lambertini C, Taborelli M, Rinaldi A, Zucca E, Catapano C, Cavalli F, Gianella-Borradori A, Maccallum DE, Bertoni F (2005) In vitro activity of cyclin-dependent kinase inhibitor CYC202 (seliciclib, R-roscovitine) in mantle cell lymphomas. Ann Oncol 16:1169–1176PubMedCrossRefGoogle Scholar
  183. Lacrima K, Rinaldi A, Vignati S, Martin V, Tibiletti MG, Gaidano G, Catapano CV, Bertoni F (2007) Cyclin-dependent kinase inhibitor seliciclib shows in vitro activity in diffuse large B-cell lymphomas. Leuk Lymphoma 48:158–167PubMedCrossRefGoogle Scholar
  184. Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW (2006) Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 9:13–22PubMedCrossRefGoogle Scholar
  185. Lapenna S, Giordano A (2009) Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 8:547–566PubMedCrossRefGoogle Scholar
  186. Larochelle S, Merrick KA, Terret ME, Wohlbold L, Barboza NM, Zhang C, Shokat KM, Jallepalli PV, Fisher RP (2007) Requirements for Cdk7 in the assembly of Cdk1/cyclin B and activation of Cdk2 revealed by chemical genetics in human cells. Mol Cell 25:839–850PubMedCrossRefGoogle Scholar
  187. Larochelle S, Amat R, Glover-Cutter K, Sanso M, Zhang C, Allen JJ, Shokat KM, Bentley DL, Fisher RP (2012) Cyclin-dependent kinase control of the initiation-to-elongation switch of RNA polymerase II. Nat Struct Mol Biol 19:1108–1115PubMedCrossRefGoogle Scholar
  188. Lassus P, Opitz-Araya X, Lazebnik Y (2002) Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science 297:1352–1354PubMedCrossRefGoogle Scholar
  189. Lavoie JN, Rivard N, L’Allemain G, Pouyssegur J (1996) A temporal and biochemical link between growth factor-activated MAP kinases, cyclin D1 induction and cell cycle entry. Prog Cell Cycle Res 2:49–58PubMedCrossRefGoogle Scholar
  190. Lazarov M, Kubo Y, Cai T, Dajee M, Tarutani M, Lin Q, Fang M, Tao S, Green CL, Khavari PA (2002) CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis. Nat Med 8:1105–1114PubMedCrossRefGoogle Scholar
  191. Lee YM, Sicinski P (2006) Targeting cyclins and cyclin-dependent kinases in cancer: lessons from mice, hopes for therapeutic applications in human. Cell Cycle 5:2110–2114PubMedCrossRefGoogle Scholar
  192. Lee YK, Isham CR, Kaufman SH, Bible KC (2006) Flavopiridol disrupts STAT3/DNA interactions, attenuates STAT3-directed transcription, and combines with the Jak kinase inhibitor AG490 to achieve cytotoxic synergy. Mol Cancer Ther 5:138–148PubMedCrossRefGoogle Scholar
  193. Lents NH, Keenan SM, Bellone C, Baldassare JJ (2002) Stimulation of the Raf/MEK/ERK cascade is necessary and sufficient for activation and Thr-160 phosphorylation of a nuclear-targeted CDK2. J Biol Chem 277:47469–47475PubMedCrossRefGoogle Scholar
  194. Lesage D, Troussard X, Sola B (2005) The enigmatic role of cyclin D1 in multiple myeloma. Int J Cancer 115:171–176PubMedCrossRefGoogle Scholar
  195. Li KK, Ng IO, Fan ST, Albrecht JH, Yamashita K, Poon RY (2002) Activation of cyclin-dependent kinases CDC2 and CDK2 in hepatocellular carcinoma. Liver 22:259–268PubMedCrossRefGoogle Scholar
  196. Li Q, Price JP, Byers SA, Cheng D, Peng J, Price DH (2005) Analysis of the large inactive P-TEFb complex indicates that it contains one 7SK molecule, a dimer of HEXIM1 or HEXIM2, and two P-TEFb molecules containing Cdk9 phosphorylated at threonine 186. J Biol Chem 280:28819–28826PubMedCrossRefGoogle Scholar
  197. Li M, Lockwood W, Zielenska M, Northcott P, Ra YS, Bouffet E, Yoshimoto M, Rutka JT, Yan H, Taylor MD, Eberhart C, Hawkins CE, Lam W, Squire JA, Huang A (2012) Multiple CDK/CYCLIND genes are amplified in medulloblastoma and supratentorial primitive neuroectodermal brain tumor. Cancer Genet 205:220–231PubMedCrossRefGoogle Scholar
  198. Lin TS, Howard OM, Neuberg DS, Kim HH, Shipp MA (2002) Seventy-two hour continuous infusion flavopiridol in relapsed and refractory mantle cell lymphoma. Leuk Lymphoma 43:793–797PubMedCrossRefGoogle Scholar
  199. Liu DX, Greene LA (2001a) Neuronal apoptosis at the G1/S cell cycle checkpoint. Cell Tissue Res 305:217–228PubMedCrossRefGoogle Scholar
  200. Liu DX, Greene LA (2001b) Regulation of neuronal survival and death by E2F-dependent gene repression and derepression. Neuron 32(3):425–438PubMedCrossRefGoogle Scholar
  201. Lopes JP, Oliveira CR, Agostinho P (2007) Role of cyclin-dependent kinase 5 in the neurodegenerative process triggered by amyloid-beta and prion peptides: implications for Alzheimer’s disease and prion-related encephalopathies. Cell Mol Neurobiol 27:943–957PubMedCrossRefGoogle Scholar
  202. Lopes JP, Oliveira CR, Agostinho P (2009) Cdk5 acts as a mediator of neuronal cell cycle re-entry triggered by amyloid-beta and prion peptides. Cell Cycle 8:97–104PubMedCrossRefGoogle Scholar
  203. Lopes JP, Oliveira CR, Agostinho P (2010) Neurodegeneration in an Abeta-induced model of Alzheimer’s disease: the role of Cdk5. Aging Cell 9(1):64–77PubMedCrossRefGoogle Scholar
  204. Lopes JP, Agostinho P (2011) Cdk5: multitasking between physiological and pathological conditions. Prog Neurobiol 94:49–63PubMedCrossRefGoogle Scholar
  205. Love S (2003) Neuronal expression of cell cycle-related proteins after brain ischaemia in man. Neurosci Lett 353:29–32PubMedCrossRefGoogle Scholar
  206. Loyer P, Trembley JH, Katona R, Kidd VJ, Lahti JM (2005) Role of CDK/cyclin complexes in transcription and RNA splicing. Cell Signal 17:1033–1051PubMedCrossRefGoogle Scholar
  207. Loyer P, Trembley JH, Grenet JA, Busson A, Corlu A, Zhao W, Kocak M, Kidd VJ, Lahti JM (2008) Characterization of cyclin L1 and L2 interactions with CDK11 and splicing factors: influence of cyclin L isoforms on splice site selection. J Biol Chem 283:7721–7732PubMedCrossRefGoogle Scholar
  208. Loyer P, Busson A, Trembley JH, Hyle J, Grenet J, Zhao W, Ribault C, Montier T, Kidd VJ, Lahti JM (2011) The RNA binding motif protein 15B (RBM15B/OTT3) is a functional competitor of serine-arginine (SR) proteins and antagonizes the positive effect of the CDK11p110-cyclin L2alpha complex on splicing. J Biol Chem 286:147–159PubMedCrossRefGoogle Scholar
  209. Lu F, Gladden AB, Diehl JA (2003) An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene. Cancer Res 63:7056–7061PubMedGoogle Scholar
  210. Lu X, Burgan WE, Cerra MA, Chuang EY, Tsai MH, Tofilon PJ, Camphausen K (2004) Transcriptional signature of flavopiridol-induced tumor cell death. Mol Cancer Ther 3:861–872PubMedGoogle Scholar
  211. Ma Y, Cress WD (2007) Transcriptional upregulation of p57 (Kip2) by the cyclin-dependent kinase inhibitor BMS-387032 is E2F dependent and serves as a negative feedback loop limiting cytotoxicity. Oncogene 26:3532–3540PubMedCrossRefGoogle Scholar
  212. Ma Y, Cress WD, Haura EB (2003) Flavopiridol-induced apoptosis is mediated through up-regulation of E2F1 and repression of Mcl-1. Mol Cancer Ther 2:73–81PubMedGoogle Scholar
  213. Ma Y, Freeman SN, Cress WD (2004) E2F4 deficiency promotes drug-induced apoptosis. Cancer Biol Ther 3:1262–1269PubMedCrossRefGoogle Scholar
  214. Maccallum DE, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A, Lane DP, Green SR (2005) Seliciclib (CYC202, R-roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res 65:5399–5407PubMedCrossRefGoogle Scholar
  215. Malumbres M, Sotillo R, Santamaria D, Galan J, Cerezo A, Ortega S, Dubus P, Barbacid M (2004) Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118:493–504PubMedCrossRefGoogle Scholar
  216. Malumbres M, Barbacid M (2005) Mammalian cyclin-dependent kinases. Trends Biochem Sci 30:630–641PubMedCrossRefGoogle Scholar
  217. Malumbres M, Barbacid M (2006) Is Cyclin D1-CDK4 kinase a bona fide cancer target? Cancer Cell 9:2–4PubMedCrossRefGoogle Scholar
  218. Malumbres M, Barbacid M (2007) Cell cycle kinases in cancer. Curr Opin Genet Dev 17:60–65PubMedCrossRefGoogle Scholar
  219. Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9:153–166PubMedCrossRefGoogle Scholar
  220. Marshall NF, Price DH (1995) Purification of P-TEFb, a transcription factor required for the transition into productive elongation. J Biol Chem 270:12335–12338PubMedCrossRefGoogle Scholar
  221. Marshall RM, Salerno D, Garriga J, Grana X (2005) Cyclin T1 expression is regulated by multiple signaling pathways and mechanisms during activation of human peripheral blood lymphocytes. J Immunol 175:6402–6411PubMedGoogle Scholar
  222. Martin A, Odajima J, Hunt SL, Dubus P, Ortega S, Malumbres M, Barbacid M (2005) Cdk2 is dispensable for cell cycle inhibition and tumor suppression mediated by p27(Kip1) and p21(Cip1). Cancer Cell 7:591–598PubMedCrossRefGoogle Scholar
  223. McClue SJ, Blake D, Clarke R, Cowan A, Cummings L, Fischer PM, MacKenzie M, Melville J, Stewart K, Wang S, Zhelev N, Zheleva D, Lane DP (2002) In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int J Cancer 102:463–468PubMedCrossRefGoogle Scholar
  224. McKinstry R, Qiao L, Yacoub A, Dai Y, Decker R, Holt S, Hagan MP, Grant S, Dent P (2002) Inhibitors of MEK1/2 interact with UCN-01 to induce apoptosis and reduce colony formation in mammary and prostate carcinoma cells. Cancer Biol Ther 1:243–253PubMedGoogle Scholar
  225. Meijer L, Borgne A, Mulner O, Chong JP, Blow JJ, Inagaki N, Inagaki M, Delcros JG, Moulinoux JP (1997) Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem 243:527–536PubMedCrossRefGoogle Scholar
  226. Merrick KA, Larochelle S, Zhang C, Allen JJ, Shokat KM, Fisher RP (2008) Distinct activation pathways confer cyclin-binding specificity on Cdk1 and Cdk2 in human cells. Mol Cell 32:662–672PubMedCrossRefGoogle Scholar
  227. Merrick KA, Fisher RP (2010a) A virtual cycle: theory and experiment converge on the exit from mitosis. F1000 Biol Rep 2:33 Google Scholar
  228. Merrick KA, Fisher RP (2010b) Putting one step before the other: distinct activation pathways for Cdk1 and Cdk2 bring order to the mammalian cell cycle. Cell Cycle 9:706–714PubMedCrossRefGoogle Scholar
  229. Merrick KA, Wohlbold L, Zhang C, Allen JJ, Horiuchi D, Huskey NE, Goga A, Shokat KM, Fisher RP (2011) Switching Cdk2 on or off with small molecules to reveal requirements in human cell proliferation. Mol Cell 42:624–636PubMedCrossRefGoogle Scholar
  230. Merrick KA, Fisher RP (2012) Why minimal is not optimal: driving the mammalian cell cycle–and drug discovery–with a physiologic CDK control network. Cell Cycle 11:2600–2605PubMedCrossRefGoogle Scholar
  231. Micheau O (2003) Cellular FLICE-inhibitory protein: an attractive therapeutic target? Expert Opin Ther Targets 7:559–573PubMedCrossRefGoogle Scholar
  232. Michels AA, Fraldi A, Li Q, Adamson TE, Bonnet F, Nguyen VT, Sedore SC, Price JP, Price DH, Lania L, Bensaude O (2004) Binding of the 7SK snRNA turns the HEXIM1 protein into a P-TEFb (CDK9/cyclin T) inhibitor. EMBO J 23:2608–2619PubMedCrossRefGoogle Scholar
  233. Mikolcevic P, Sigl R, Rauch V, Hess MW, Pfaller K, Barisic M, Pelliniemi LJ, Boesl M, Geley S (2012) Cyclin-dependent kinase 16/PCTAIRE kinase 1 is activated by cyclin Y and is essential for spermatogenesis. Mol Cell Biol 32:868–879PubMedCrossRefGoogle Scholar
  234. Misra RN, Xiao HY, Kim KS, Lu S, Han WC, Barbosa SA, Hunt JT, Rawlins DB, Shan W, Ahmed SZ, Qian L, Chen BC, Zhao R, Bednarz MS, Kellar KA, Mulheron JG, Batorsky R, Roongta U, Kamath A, Marathe P, Ranadive SA, Sack JS, Tokarski JS, Pavletich NP, Lee FY, Webster KR, Kimball SD (2004) N-(Cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent. J Med Chem 47:1719–1728 Google Scholar
  235. Mitchell C, Hamed HA, Cruickshanks N, Tang Y, Bareford MD, Hubbard N, Tye G, Yacoub A, Dai Y, Grant S, Dent P (2011) Simultaneous exposure of transformed cells to SRC family inhibitors and CHK1 inhibitors causes cell death. Cancer Biol Ther 12:215–228PubMedCrossRefGoogle Scholar
  236. Morris MC, Gondeau C, Tainer JA, Divita G (2002) Kinetic mechanism of activation of the Cdk2/cyclin A complex. Key role of the C-lobe of the Cdk. J Biol Chem 277:23847–23853Google Scholar
  237. Mukhopadhyay P, Ali MA, Nandi A, Carreon P, Choy H, Saha D (2006) The cyclin-dependent kinase 2 inhibitor down-regulates interleukin-1beta-mediated induction of cyclooxygenase-2 expression in human lung carcinoma cells. Cancer Res 66:1758–1766PubMedCrossRefGoogle Scholar
  238. Newcomb EW (2004) Flavopiridol: pleiotropic biological effects enhance its anti-cancer activity. Anticancer Drugs 15:411–419PubMedCrossRefGoogle Scholar
  239. Newcomb EW, Ali MA, Schnee T, Lan L, Lukyanov Y, Fowkes M, Miller DC, Zagzag D (2005) Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1alpha expression in human glioma cells by a proteasome-independent pathway: implications for in vivo therapy. Neuro Oncol 7:225–235PubMedCrossRefGoogle Scholar
  240. Ng MH, Chung YF, Lo KW, Wickham NW, Lee JC, Huang DP (1997) Frequent hypermethylation of p16 and p15 genes in multiple myeloma. Blood 89:2500–2506PubMedGoogle Scholar
  241. Nguyen VT, Kiss T, Michels AA, Bensaude O (2001) 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature 414:322–325PubMedCrossRefGoogle Scholar
  242. Nguyen T, Dai Y, Attkisson E, Kramer L, Jordan N, Nguyen N, Kolluri N, Muschen M, Grant S (2011) HDAC inhibitors potentiate the activity of the BCR/ABL kinase inhibitor KW-2449 in imatinib-sensitive or -resistant BCR/ABL+ leukemia cells in vitro and in vivo. Clin Cancer Res 17:3219–3232PubMedCrossRefGoogle Scholar
  243. Nikolic M, Tsai LH (2000) Activity and regulation of p35/Cdk5 kinase complex. Methods Enzymol 325:200–213PubMedCrossRefGoogle Scholar
  244. Nurse P (2012) Finding CDK: linking yeast with humans. Nat Cell Biol 14:776PubMedCrossRefGoogle Scholar
  245. Odajima J, Wills ZP, Ndassa YM, Terunuma M, Kretschmannova K, Deeb TZ, Geng Y, Gawrzak S, Quadros IM, Newman J, Das M, Jecrois ME, Yu Q, Li N, Bienvenu F, Moss SJ, Greenberg ME, Marto JA, Sicinski P (2011) Cyclin E constrains Cdk5 activity to regulate synaptic plasticity and memory formation. Dev Cell 21:655–668PubMedCrossRefGoogle Scholar
  246. Oikonomakos NG, Schnier JB, Zographos SE, Skamnaki VT, Tsitsanou KE, Johnson LN (2000) Flavopiridol inhibits glycogen phosphorylase by binding at the inhibitor site. J Biol Chem 275:34566–34573PubMedCrossRefGoogle Scholar
  247. Oka K, Ohno T, Yamaguchi M, Mahmud N, Miwa H, Kita K, Shiku H, Shirakawa S (1996) PRAD1/cyclin D1 gene overexpression in mantle cell lymphoma. Leuk Lymphoma 21:37–42PubMedCrossRefGoogle Scholar
  248. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435:677–681PubMedCrossRefGoogle Scholar
  249. Ortega S, Malumbres M, Barbacid M (2002) Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta 1602:73–87PubMedGoogle Scholar
  250. Ortega S, Prieto I, Odajima J, Martin A, Dubus P, Sotillo R, Barbero JL, Malumbres M, Barbacid M (2003) Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 35:25–31PubMedCrossRefGoogle Scholar
  251. Ou CY, Poon VY, Maeder CI, Watanabe S, Lehrman EK, Fu AK, Park M, Fu WY, Jorgensen EM, Ip NY, Shen K (2010) Two cyclin-dependent kinase pathways are essential for polarized trafficking of presynaptic components. Cell 141:846–858PubMedCrossRefGoogle Scholar
  252. Park M, Watanabe S, Poon VY, Ou CY, Jorgensen EM, Shen K (2011) CYY-1/cyclin Y and CDK-5 differentially regulate synapse elimination and formation for rewiring neural circuits. Neuron 70:742–757PubMedCrossRefGoogle Scholar
  253. Parry D, Guzi T, Shanahan F, Davis N, Prabhavalkar D, Wiswell D, Seghezzi W, Paruch K, Dwyer MP, Doll R, Nomeir A, Windsor W, Fischmann T, Wang Y, Oft M, Chen T, Kirschmeier P, Lees EM (2010) Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther 9:2344–2353PubMedCrossRefGoogle Scholar
  254. Patel SA, Simon MC (2010) Functional analysis of the Cdk7.cyclin H.Mat1 complex in mouse embryonic stem cells and embryos. J Biol Chem 285:15587–15598Google Scholar
  255. Patel V, Senderowicz AM, Pinto D Jr, Igishi T, Raffeld M, Quintanilla-Martinez L, Ensley JF, Sausville EA, Gutkind JS (1998) Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. J Clin Invest 102:1674–1681PubMedCrossRefGoogle Scholar
  256. Patel V, Lahusen T, Leethanakul C, Igishi T, Kremer M, Quintanilla-Martinez L, Ensley JF, Sausville EA, Gutkind JS, Senderowicz AM (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 8:3549–3560PubMedGoogle Scholar
  257. Pei XY, Dai Y, Grant S (2004) The small-molecule Bcl-2 inhibitor HA14-1 interacts synergistically with flavopiridol to induce mitochondrial injury and apoptosis in human myeloma cells through a free radical-dependent and Jun NH2-terminal kinase-dependent mechanism. Mol Cancer Ther 3:1513–1524PubMedGoogle Scholar
  258. Pei XY, Dai Y, Rahmani M, Li W, Dent P, Grant S (2005) The farnesyltransferase inhibitor L744832 potentiates UCN-01-induced apoptosis in human multiple myeloma cells. Clin Cancer Res 11:4589–4600PubMedCrossRefGoogle Scholar
  259. Pei XY, Li W, Dai Y, Dent P, Grant S (2006) Dissecting the roles of checkpoint kinase 1/CDC2 and mitogen-activated protein kinase kinase 1/2/extracellular signal-regulated kinase 1/2 in relation to 7-hydroxystaurosporine-induced apoptosis in human multiple myeloma cells. Mol Pharmacol 70:1965–1973PubMedCrossRefGoogle Scholar
  260. Pei XY, Dai Y, Tenorio S, Lu J, Harada H, Dent P, Grant S (2007) MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism. Blood 110:2092–2101PubMedCrossRefGoogle Scholar
  261. Pei XY, Dai Y, Youssefian LE, Chen S, Bodie WW, Takabatake Y, Felthousen J, Almenara JA, Kramer LB, Dent P, Grant S (2011) Cytokinetically quiescent (G0/G1) human multiple myeloma cells are susceptible to simultaneous inhibition of Chk1 and MEK1/2. Blood 118:5189–5200PubMedCrossRefGoogle Scholar
  262. Peng J, Zhu Y, Milton JT, Price DH (1998) Identification of multiple cyclin subunits of human P-TEFb. Genes Dev 12:755–762PubMedCrossRefGoogle Scholar
  263. Pepper C, Thomas A, Hoy T, Fegan C, Bentley P (2001) Flavopiridol circumvents Bcl-2 family mediated inhibition of apoptosis and drug resistance in B-cell chronic lymphocytic leukaemia. Br J Haematol 114:70–77PubMedCrossRefGoogle Scholar
  264. Perez PC, Caceres RA, Canduri F, de Azevedo WFJ (2009) Molecular modeling and dynamics simulation of human cyclin-dependent kinase 3 complexed with inhibitors. Comput Biol Med 39:130–140PubMedCrossRefGoogle Scholar
  265. Perez-Simon JA, Garcia-Sanz R, Tabernero MD, Almeida J, Gonzalez M, Fernandez-Calvo J, Moro MJ, Hernandez JM, San Miguel JF, Orfao A (1998) Prognostic value of numerical chromosome aberrations in multiple myeloma: a FISH analysis of 15 different chromosomes. Blood 91:3366–3371Google Scholar
  266. Peterlin BM, Price DH (2006) Controlling the elongation phase of transcription with P-TEFb. Mol Cell 23:297–305PubMedCrossRefGoogle Scholar
  267. Price DH (2000) P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol Cell Biol 20:2629–2634PubMedCrossRefGoogle Scholar
  268. Radu A, Neubauer V, Akagi T, Hanafusa H, Georgescu MM (2003) PTEN induces cell cycle arrest by decreasing the level and nuclear localization of cyclin D1. Mol Cell Biol 23:6139–6149PubMedCrossRefGoogle Scholar
  269. Raje N, Kumar S, Hideshima T, Roccaro A, Ishitsuka K, Yasui H, Shiraishi N, Chauhan D, Munshi NC, Green SR, Anderson KC (2005) Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood 106:1042–1047PubMedCrossRefGoogle Scholar
  270. Rashidian J, Iyirhiaro G, Aleyasin H, Rios M, Vincent I, Callaghan S, Bland RJ, Slack RS, During MJ, Park DS (2005) Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo. Proc Natl Acad Sci USA 102:14080–14085PubMedCrossRefGoogle Scholar
  271. Raynaud FI, Whittaker SR, Fischer PM, McClue S, Walton MI, Barrie SE, Garrett MD, Rogers P, Clarke SJ, Kelland LR, Valenti M, Brunton L, Eccles S, Lane DP, Workman P (2005) In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202. Clin Cancer Res 11:4875–4887PubMedCrossRefGoogle Scholar
  272. Reed JC (2003) Apoptosis-targeted therapies for cancer. Cancer Cell 3(1):17–22PubMedCrossRefGoogle Scholar
  273. Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB (2007) p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 11:175–189PubMedCrossRefGoogle Scholar
  274. Ren S, Rollins BJ (2004) Cyclin C/cdk3 promotes Rb-dependent G0 exit. Cell 117:239–251PubMedCrossRefGoogle Scholar
  275. Ribas J, Boix J, Meijer L (2006) (R)-Roscovitine (CYC202, seliciclib) sensitizes SH-SY5Y neuroblastoma cells to nutlin-3-induced apoptosis. Exp Cell Res 312:2394–2400PubMedCrossRefGoogle Scholar
  276. Rodriguez-Bravo V, Guaita-Esteruelas S, Florensa R, Bachs O, Agell N (2006) Chk1- and claspin-dependent but ATR/ATM- and Rad17-independent DNA replication checkpoint response in HeLa cells. Cancer Res 66:8672–8679 PubMedCrossRefGoogle Scholar
  277. Rosato RR, Dai Y, Almenara JA, Maggio SC, Grant S (2004) Potent antileukemic interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation. Leukemia 18:1780–1788PubMedCrossRefGoogle Scholar
  278. Rosato RR, Almenara JA, Maggio SC, Atadja P, Craig R, Vrana J, Dent P, Grant S (2005) Potentiation of the lethality of the histone deacetylase inhibitor LAQ824 by the cyclin-dependent kinase inhibitor roscovitine in human leukemia cells. Mol Cancer Ther 4:1772–1785PubMedCrossRefGoogle Scholar
  279. Rossi AG, Sawatzky DA, Walker A, Ward C, Sheldrake TA, Riley NA, Caldicott A, Martinez-Losa M, Walker TR, Duffin R, Gray M, Crescenzi E, Martin MC, Brady HJ, Savill JS, Dransfield I, Haslett C (2006) Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med 12:1056–1064PubMedCrossRefGoogle Scholar
  280. Roychowdhury S, Iyer MK, Robinson DR, Lonigro RJ, Wu YM, Cao X, Kalyana-Sundaram S, Sam L, Balbin OA, Quist MJ, Barrette T, Everett J, Siddiqui J, Kunju LP, Navone N, Araujo JC, Troncoso P, Logothetis CJ, Innis JW, Smith DC, Lao CD, Kim SY, Roberts JS, Gruber SB, Pienta KJ, Talpaz M, Chinnaiyan AM (2011) Personalized oncology through integrative high-throughput sequencing: a pilot study. Sci Transl Med 3:111ra121Google Scholar
  281. Sage J (2004) Cyclin C makes an entry into the cell cycle. Dev Cell 6:607–608PubMedCrossRefGoogle Scholar
  282. Sampath D, Cortes J, Estrov Z, Du M, Shi Z, Andreeff M, Gandhi V, Plunkett W (2006) Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial. Blood 107:2517–2524PubMedCrossRefGoogle Scholar
  283. Sandal T (2002) Molecular aspects of the mammalian cell cycle and cancer. Oncologist 7:73–81PubMedCrossRefGoogle Scholar
  284. Santamaria D, Barriere C, Cerqueira A, Hunt S, Tardy C, Newton K, Caceres JF, Dubus P, Malumbres M, Barbacid M (2007) Cdk1 is sufficient to drive the mammalian cell cycle. Nature 448:811–815PubMedCrossRefGoogle Scholar
  285. Sarasquete ME, Garcia-Sanz R, Armellini A, Fuertes M, Martin-Jimenez P, Sierra M, Del Carmen CM, Alcoceba M, Balanzategui A, Ortega F, Hernandez JM, Sureda A, Palomera L, Gonzalez M, San Miguel JF (2006) The association of increased p14ARF/p16INK4a and p15INK4a gene expression with proliferative activity and the clinical course of multiple myeloma. Haematologica 91:1551–1554Google Scholar
  286. Sato S, Fujita N, Tsuruo T (2002) Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene 21:1727–1738PubMedCrossRefGoogle Scholar
  287. Sato K, Zhu YS, Saito T, Yotsumoto K, Asada A, Hasegawa M, Hisanaga S (2007) Regulation of membrane association and kinase activity of Cdk5-p35 by phosphorylation of p35. J Neurosci Res 85:3071–3078PubMedCrossRefGoogle Scholar
  288. Sato K, Minegishi S, Takano J, Plattner F, Saito T, Asada A, Kawahara H, Iwata N, Saido TC, Hisanaga S (2011) Calpastatin, an endogenous calpain-inhibitor protein, regulates the cleavage of the Cdk5 activator p35 to p25. J Neurochem 117:504–515PubMedCrossRefGoogle Scholar
  289. Sausville EA (2002) Complexities in the development of cyclin-dependent kinase inhibitor drugs. Trends Mol Med 8:S32–S37PubMedCrossRefGoogle Scholar
  290. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17:1675–1687PubMedCrossRefGoogle Scholar
  291. Schneider E, Kartarius S, Schuster N, Montenarh M (2002) The cyclin H/cdk7/Mat1 kinase activity is regulated by CK2 phosphorylation of cyclin H. Oncogene 21:5031–5037PubMedCrossRefGoogle Scholar
  292. Schwartz GK, Shah MA (2005) Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol 23:9408–9421PubMedCrossRefGoogle Scholar
  293. Schwartz GK, Ilson D, Saltz L, O’Reilly E, Tong W, Maslak P, Werner J, Perkins P, Stoltz M, Kelsen D (2001) Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. J Clin Oncol 19:1985–1992PubMedGoogle Scholar
  294. Sedlacek HH (2001) Mechanisms of action of flavopiridol. Crit Rev Oncol Hematol 38:139–170PubMedCrossRefGoogle Scholar
  295. Semenov I, Akyuz C, Roginskaya V, Chauhan D, Corey SJ (2002) Growth inhibition and apoptosis of myeloma cells by the CDK inhibitor flavopiridol. Leuk Res 26:271–280PubMedCrossRefGoogle Scholar
  296. Senderowicz AM (2002) The cell cycle as a target for cancer therapy: basic and clinical findings with the small molecule inhibitors flavopiridol and UCN-01. Oncologist 7:12–19PubMedCrossRefGoogle Scholar
  297. Senderowicz AM (2003) Small-molecule cyclin-dependent kinase modulators. Oncogene 22:6609–6620PubMedCrossRefGoogle Scholar
  298. Senderowicz AM, Sausville EA (2000) Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst 92:376–387PubMedCrossRefGoogle Scholar
  299. Shao J, Sheng H, DuBois RN, Beauchamp RD (2000) Oncogenic Ras-mediated cell growth arrest and apoptosis are associated with increased ubiquitin-dependent cyclin D1 degradation. J Biol Chem 275:22916–22924PubMedCrossRefGoogle Scholar
  300. Shapiro GI (2004) Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol. Clin Cancer Res 10:4270s–4275sPubMedCrossRefGoogle Scholar
  301. Shapiro GI (2006) Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 24:1770–1783PubMedCrossRefGoogle Scholar
  302. Shapiro GI, Supko JG, Patterson A, Lynch C, Lucca J, Zacarola PF, Muzikansky A, Wright JJ, Lynch TJ Jr, Rollins BJ (2001) A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer. Clin Cancer Res 7:1590–1599PubMedGoogle Scholar
  303. Shi Y, Sharma A, Wu H, Lichtenstein A, Gera J (2005) Cyclin D1 and c-myc internal ribosome entry site (IRES)-dependent translation is regulated by AKT activity and enhanced by rapamycin through a p38. J Biol Chem 280:10964–10973PubMedCrossRefGoogle Scholar
  304. Shu F, Lv S, Qin Y, Ma X, Wang X, Peng X, Luo Y, Xu BE, Sun X, Wu J (2007) Functional characterization of human PFTK1 as a cyclin-dependent kinase. Proc Natl Acad Sci USA 104:9248–9253PubMedCrossRefGoogle Scholar
  305. Sonoki T, Harder L, Horsman DE, Karran L, Taniguchi I, Willis TG, Gesk S, Steinemann D, Zucca E, Schlegelberger B, Sole F, Mungall AJ, Gascoyne RD, Siebert R, Dyer MJ (2001) Cyclin D3 is a target gene of t(6;14)(p21.1;q32.3) of mature B-cell malignancies. Blood 98:2837–2844PubMedCrossRefGoogle Scholar
  306. Strasser A, O’Connor L, Dixit VM (2000) Apoptosis signaling. Annu Rev Biochem 69:217–245PubMedCrossRefGoogle Scholar
  307. Takada Y, Aggarwal BB (2004) Flavopiridol inhibits NF-kappaB activation induced by various carcinogens and inflammatory agents through inhibition of IkappaBalpha kinase and p65 phosphorylation: abrogation of cyclin D1, cyclooxygenase-2, and matrix metalloprotease-9. J Biol Chem 279:4750–4759PubMedCrossRefGoogle Scholar
  308. Takahashi-Yanaga F, Mori J, Matsuzaki E, Watanabe Y, Hirata M, Miwa Y, Morimoto S, Sasaguri T (2006) Involvement of GSK-3beta and DYRK1B in differentiation-inducing factor-3-induced phosphorylation of cyclin D1 in HeLa cells. J Biol Chem 281:38489–38497PubMedCrossRefGoogle Scholar
  309. Tan AR, Headlee D, Messmann R, Sausville EA, Arbuck SG, Murgo AJ, Melillo G, Zhai S, Figg WD, Swain SM, Senderowicz AM (2002) Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms. J Clin Oncol 20:4074–4082PubMedCrossRefGoogle Scholar
  310. Tang L, Li MH, Cao P, Wang F, Chang WR, Bach S, Reinhardt J, Ferandin Y, Galons H, Wan Y, Gray N, Meijer L, Jiang T, Liang DC (2005) Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. J Biol Chem 280:31220–31229PubMedCrossRefGoogle Scholar
  311. Tang Y, Dai Y, Grant S, Dent P (2012a) Enhancing CHK1 inhibitor lethality in glioblastoma. Cancer Biol Ther 13:379–388PubMedCrossRefGoogle Scholar
  312. Tang Y, Hamed HA, Poklepovic A, Dai Y, Grant S, Dent P (2012b) Poly(ADP-ribose) polymerase 1 modulates the lethality of CHK1 inhibitors in mammary tumors. Mol Pharmacol 82:322–332PubMedCrossRefGoogle Scholar
  313. Tasaka T, Berenson J, Vescio R, Hirama T, Miller CW, Nagai M, Takahara J, Koeffler HP (1997) Analysis of the p16INK4A, p15INK4B and p18INK4C genes in multiple myeloma. Br J Haematol 96:98–102PubMedCrossRefGoogle Scholar
  314. Tashiro E, Tsuchiya A, Imoto M (2007) Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression. Cancer Sci 98:629–635PubMedCrossRefGoogle Scholar
  315. Tetsu O, McCormick F (2003) Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 3:233–245PubMedCrossRefGoogle Scholar
  316. Tian DS, Yu ZY, Xie MJ, Bu BT, Witte OW, Wang W (2006) Suppression of astroglial scar formation and enhanced axonal regeneration associated with functional recovery in a spinal cord injury rat model by the cell cycle inhibitor olomoucine. J Neurosci Res 84:1053–1063PubMedCrossRefGoogle Scholar
  317. Tian DS, Xie MJ, Yu ZY, Zhang Q, Wang YH, Chen B, Chen C, Wang W (2007) Cell cycle inhibition attenuates microglia induced inflammatory response and alleviates neuronal cell death after spinal cord injury in rats. Brain Res 1135:177–185PubMedCrossRefGoogle Scholar
  318. Trembley JH, Hu D, Slaughter CA, Lahti JM, Kidd VJ (2003) Casein kinase 2 interacts with cyclin-dependent kinase 11 (CDK11) in vivo and phosphorylates both the RNA polymerase II carboxyl-terminal domain and CDK11 in vitro. J Biol Chem 278:2265–2270PubMedCrossRefGoogle Scholar
  319. Trembley JH, Loyer P, Hu D, Li T, Grenet J, Lahti JM, Kidd VJ (2004) Cyclin dependent kinase 11 in RNA transcription and splicing. Prog Nucleic Acid Res Mol Biol 77:263–288PubMedCrossRefGoogle Scholar
  320. Tricot G, Barlogie B, Jagannath S, Bracy D, Mattox S, Vesole DH, Naucke S, Sawyer JR (1995) Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities. Blood 86:4250–4256PubMedGoogle Scholar
  321. Tse AN, Carvajal R, Schwartz GK (2007) Targeting checkpoint kinase 1 in cancer therapeutics. Clin Cancer Res 13:1955–1960PubMedCrossRefGoogle Scholar
  322. Tsutsui T, Fukasawa R, Tanaka A, Hirose Y, Ohkuma Y (2011) Identification of target genes for the CDK subunits of the Mediator complex. Genes CellsGoogle Scholar
  323. Urashima M, Ogata A, Chauhan D, Vidriales MB, Teoh G, Hoshi Y, Schlossman RL, DeCaprio JA, Anderson KC (1996) Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein. Blood 88:2219–2227PubMedGoogle Scholar
  324. van Deursen JM (2007) Rb loss causes cancer by driving mitosis mad. Cancer Cell 11:1–3PubMedCrossRefGoogle Scholar
  325. Van Herreweghe E, Egloff S, Goiffon I, Jady BE, Froment C, Monsarrat B, Kiss T (2007) Dynamic remodelling of human 7SK snRNP controls the nuclear level of active P-TEFb. EMBO J 26:3570–3580PubMedCrossRefGoogle Scholar
  326. Vaux DL, Silke J (2005) IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol 6:287–297PubMedCrossRefGoogle Scholar
  327. Verhagen AM, Vaux DL (2002) Cell death regulation by the mammalian IAP antagonist Diablo/Smac. Apoptosis 7:163–166PubMedCrossRefGoogle Scholar
  328. Vogel C, Hager C, Bastians H (2007) Mechanisms of mitotic cell death induced by chemotherapy-mediated G2 checkpoint abrogation. Cancer Res 67:339–345PubMedCrossRefGoogle Scholar
  329. Wallenfang MR, Seydoux G (2002) cdk-7 Is required for mRNA transcription and cell cycle progression in Caenorhabditis elegans embryos. Proc Natl Acad Sci USA 99:5527–5532PubMedCrossRefGoogle Scholar
  330. Wang JM, Chao JR, Chen W, Kuo ML, Yen JJ, Yang-Yen HF (1999) The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB. Mol Cell Biol 19:6195–6206PubMedGoogle Scholar
  331. Wartiovaara K, Barnabe-Heider F, Miller FD, Kaplan DR (2002) N-myc promotes survival and induces S-phase entry of postmitotic sympathetic neurons. J Neurosci 22:815–824PubMedGoogle Scholar
  332. Wesierska-Gadek J, Kramer MP (2012) The impact of CDK inhibition in human malignancies associated with pronounced defects in apoptosis: advantages of multi-targeting small molecules. Future Med Chem 4:395–424PubMedCrossRefGoogle Scholar
  333. Wesierska-Gadek J, Krystof V (2009) Selective cyclin-dependent kinase inhibitors discriminating between cell cycle and transcriptional kinases: future reality or utopia? Ann N Y Acad Sci 1171:228–241]PubMedCrossRefGoogle Scholar
  334. Wesierska-Gadek J, Maurer M (2011) Promotion of apoptosis in cancer cells by selective purine-derived pharmacological CDK inhibitors: one outcome, many mechanisms. Curr Pharm Des 17:256–271PubMedCrossRefGoogle Scholar
  335. Wesierska-Gadek J, Maurer M, Zulehner N, Komina O (2011) Whether to target single or multiple CDKs for therapy? That is the question. J Cell Physiol 226:341–349PubMedCrossRefGoogle Scholar
  336. Whittaker SR, Walton MI, Garrett MD, Workman P (2004) The cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of cyclin D1, and activates the mitogen-activated protein kinase pathway. Cancer Res 64:262–272PubMedCrossRefGoogle Scholar
  337. Wohlbold L, Merrick KA, De S, Amat R, Kim JH, Larochelle S, Allen JJ, Zhang C, Shokat KM, Petrini JH, Fisher RP (2012) Chemical genetics reveals a specific requirement for cdk2 activity in the DNA damage response and identifies nbs1 as a cdk2 substrate in human cells. PLoS Genet 8:e1002935PubMedCrossRefGoogle Scholar
  338. Wolfel T, Hauer M, Schneider J, Serrano M, Wolfel C, Klehmann-Hieb E, De PE, Hankeln T, Meyer zum Buschenfelde KH, Beach D (1995) A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269:1281–1284Google Scholar
  339. Xu W, Ji JY (2011) Dysregulation of CDK8 and Cyclin C in tumorigenesis. J Genet Genomics 38:439–452PubMedCrossRefGoogle Scholar
  340. Yamada M, Saito T, Sato Y, Kawai Y, Sekigawa A, Hamazumi Y, Asada A, Wada M, Doi H, Hisanaga S (2007) Cdk5–p39 is a labile complex with the similar substrate specificity to Cdk5–p35. J Neurochem 102:1477–1487Google Scholar
  341. Yang Y, Geldmacher DS, Herrup K (2001a) DNA replication precedes neuronal cell death in Alzheimer’s disease. J Neurosci 21:2661–2668PubMedGoogle Scholar
  342. Yang Z, Zhu Q, Luo K, Zhou Q (2001b) The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature 414:317–322PubMedCrossRefGoogle Scholar
  343. Yu Q, Sicinski P (2004) Mammalian cell cycles without cyclin E-CDK2. Cell Cycle 3:292–295PubMedGoogle Scholar
  344. Yu C, Dai Y, Dent P, Grant S (2002a) Coadministration of UCN-01 with MEK1/2 inhibitors potently induces apoptosis in BCR/ABL+ leukemia cells sensitive and resistant to ST1571. Cancer Biol Ther 1:674–682PubMedGoogle Scholar
  345. Yu Q, La RJ, Zhang H, Takemura H, Kohn KW, Pommier Y (2002b) UCN-01 inhibits p53 up-regulation and abrogates gamma-radiation-induced G(2)-M checkpoint independently of p53 by targeting both of the checkpoint kinases, Chk2 and Chk1. Cancer Res 62:5743–5748PubMedGoogle Scholar
  346. Yu C, Rahmani M, Dai Y, Conrad D, Krystal G, Dent P, Grant S (2003) The lethal effects of pharmacological cyclin-dependent kinase inhibitors in human leukemia cells proceed through a phosphatidylinositol 3-kinase/Akt-dependent process. Cancer Res 63:1822–1833PubMedGoogle Scholar
  347. Yu Q, Sicinska E, Geng Y, Ahnstrom M, Zagozdzon A, Kong Y, Gardner H, Kiyokawa H, Harris LN, Stal O, Sicinski P (2006) Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9:23–32PubMedCrossRefGoogle Scholar
  348. Yuan Z, Becker EB, Merlo P, Yamada T, DiBacco S, Konishi Y, Schaefer EM, Bonni A (2008) Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science 319:1665–1668PubMedCrossRefGoogle Scholar
  349. Zamzami N, Kroemer G (2001) The mitochondrion in apoptosis: how Pandora’s box opens. Nat Rev Mol Cell Biol 2:67–71PubMedCrossRefGoogle Scholar
  350. Zhai S, Senderowicz AM, Sausville EA, Figg WD (2002) Flavopiridol, a novel cyclin-dependent kinase inhibitor, in clinical development. Ann Pharmacother 36:905–911PubMedCrossRefGoogle Scholar
  351. Zhang B, Gojo I, Fenton RG (2002) Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood 99:1885–1893PubMedCrossRefGoogle Scholar
  352. Zhao B, Bower MJ, McDevitt PJ, Zhao H, Davis ST, Johanson KO, Green SM, Concha NO, Zhou BB (2002) Structural basis for Chk1 inhibition by UCN-01. J Biol Chem 277:46609–46615PubMedCrossRefGoogle Scholar
  353. Zhou BB, Bartek J (2004) Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat Rev Cancer 4:216–225PubMedCrossRefGoogle Scholar
  354. Zhu YS, Saito T, Asada A, Maekawa S, Hisanaga S (2005) Activation of latent cyclin-dependent kinase 5 (Cdk5)-p35 complexes by membrane dissociation. J Neurochem 94:1535–1545PubMedCrossRefGoogle Scholar
  355. Zhu Z, Zhang Q, Yu Z, Zhang L, Tian D, Zhu S, Bu B, Xie M, Wang W (2007) Inhibiting cell cycle progression reduces reactive astrogliosis initiated by scratch injury in vitro and by cerebral ischemia in vivo. Glia 55:546–558PubMedCrossRefGoogle Scholar
  356. Zou H, Li Y, Liu X, Wang X (1999) An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 274:11549–11556PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of MedicineVirginia Commonwealth University Massey Cancer CenterRichmondUSA
  2. 2.Department of Neurosurgery, Daping Hospital, Institute of Field SurgeryThird Military Medical UniversityYuzhong District, Chongqing China

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