Promotion of apoptosis in cancer cells by selective purine-derived pharmacological CDK inhibitors: One outcome, many mechanisms

Current Pharmaceutical Design

Volumn 17, Issue 3, 2011, Pages 256-271

  Wesierska Gadek, Józefa ^a   Maurer, Margarita ^a  

^a MEDICAL UNIVERSITY OF VIENNA   (Austria)

Author keywords

Cdk7; Cdk9; G2 cell cycle arrest; Iaps; P53 dependent apoptosis; Rnap II; Survivin; Transcriptional elongation

Indexed keywords

APOPTOTIC PROTEASE ACTIVATING FACTOR 1; BETA CATENIN; CASPASE 3; CASPASE 7; CASPASE 8; CASPASE 9; CD59 ANTIGEN; CYCLIN B1; CYCLIN DEPENDENT KINASE; CYCLIN DEPENDENT KINASE 1; CYCLIN DEPENDENT KINASE 2 INHIBITOR; CYCLIN DEPENDENT KINASE 9; CYCLIN DEPENDENT KINASE INHIBITOR; CYTOCHROME C; ESTROGEN RECEPTOR ALPHA; INHIBITOR OF APOPTOSIS PROTEIN; INHIBITOR OF APOPTOSIS PROTEIN 1; INHIBITOR OF APOPTOSIS PROTEIN 2; LIVIN; PROTEIN BAD; PROTEIN BAX; PROTEIN NOXA; PROTEIN P53; PUMA PROTEIN; ROSCOVITINE; STAT3 PROTEIN; SURVIVIN; TRANSCRIPTION FACTOR E2F; UNINDEXED DRUG; X LINKED INHIBITOR OF APOPTOSIS;

APOPTOSIS; ARTICLE; AUTOPHAGY; CANCER CELL; CANCER THERAPY; CARDIOVASCULAR DISEASE; CELL CYCLE; CELL CYCLE ARREST; CELL CYCLE PROGRESSION; CELL CYCLE S PHASE; CELL PROLIFERATION; CELL SURVIVAL; CHRONIC LYMPHATIC LEUKEMIA; DEGENERATIVE DISEASE; DNA REPAIR; DNA REPLICATION; ENZYME INHIBITION; ENZYME REGULATION; HUMAN; MITOCHONDRION; MITOSIS; MULTIPLE MYELOMA; NEUROPROTECTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEIN STABILITY; SIGNAL TRANSDUCTION;

ANIMALS; APOPTOSIS; CELL CYCLE; CYCLIN-DEPENDENT KINASES; HUMANS; MICE; MOLECULAR TARGETED THERAPY; NEOPLASMS; PHOSPHORYLATION; PROTEIN KINASE INHIBITORS; RATS;

EID: 79958199914     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161211795049714     Document Type: Article

References (236)

1. Norbury C, Nurse P. Animal cell cycles and their control. AnnuRev Biochem 1992; 61: 441-70.
2. Morgan DO. Cyclin-dependent kinases: engines, clocks, andmicroprocessors. Annu Rev Cell Dev Biol 1997; 13: 261-91.
3. Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycleregulators and beyond. Dev Cell 2008; 14: 159-69.
4. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100: 57-70.
5. Galons H, Oumata N, Meijer L. Cyclin-dependent kinaseinhibitors: a survey of recent patent literature. Expert Opin Ther Pat 2010; 20: 377-404.
6. Johnson N, Shapiro GI. Cyclin-dependent kinases (cdks) and theDNA damage response: rationale for cdk inhibitor-chemotherapycombinations as an anticancer strategy for solid tumors. ExpertOpin Ther Targets 2010; 14: 1199-212.
7. Wesierska-Gadek J, Schmid G. Dual action of the inhibitors ofcyclin-dependent kinases: targeting of the cell-cycle progressionand activation of wild-type p53 protein. Expert Opin InvestigDrugs 2006; 15: 23-38.
8. Wesierska-Gadek J, Maurer M, Zulehner N, Komina O. Whether totarget single or multiple CDKs for therapy? That is the question. JCell Physiol 2011; 226: 341-9.
9. Caligaris-Cappio F. Biology of chronic lymphocytic leukemia. RevClin Exp Hematol 2000; 4: 5-21.
10. Alvi AJ, Austen B, Weston VJ, et al. A novel CDK inhibitor,CYC202 (R-roscovitine), overcomes the defect in p53-dependentapoptosis in B-CLL by down-regulation of genes involved intranscription regulation and survival. Blood 2005; 105: 4484-91.
11. Hahntow IN, Schneller F, Oelsner M, et al. Cyclin-dependentkinase inhibitor Roscovitine induces apoptosis in chroniclymphocytic leukemia cells. Leukemia 2004; 18: 747-55.
12. Ribas J, Boix J, Meijer L. (R)-roscovitine (CYC202, Seliciclib)sensitizes SH-SY5Y neuroblastoma cells to nutlin-3-inducedapoptosis. Exp Cell Res 2006; 312: 2394-400.
13. Rogalinska M, Blonski JZ, Komina O, et al. R-roscovitine(Seliciclib) affects CLL cells more strongly than combinations offludarabine or cladribine with cyclophosphamide: Inhibition ofCDK7 sensitizes leukemic cells to caspase-dependent apoptosis. JCell Biochem 2010; 109: 217-35.
14. Weingrill E, Wolfler A, Strunk D, Linkesch W, Sill H, LiebmannPM. Roscovitine in B-chronic lymphocytic leukemia cells: highapoptosis-inducing efficacy and synergism with alemtuzumabindependent of the patients' pretreatment status. Haematologica 2007; 92: 1286-8.
15. Malumbres M, Pevarello P, Barbacid M, Bischoff JR. CDKinhibitors in cancer therapy: what is next? Trends Pharmacol Sci 2008; 29: 16-21.
16. W-sierska-G-dek J, Chamrád I, Kry-tof V. Novel potentpharmacological cyclin-dependent kinase inhibitors. FutureMedicinal Chemistry 2009; 1: 1561-1581.
17. LaCasse EC, Mahoney DJ, Cheung HH, Plenchette S, Baird S,Korneluk RG. IAP-targeted therapies for cancer. Oncogene 2008;27: 6252-75.
18. Hunter AM, LaCasse EC, Korneluk RG. The inhibitors ofapoptosis (IAPs) as cancer targets. Apoptosis 2007; 12: 1543-68.
19. Straub CS. Targeting IAPs as an Approach to Anti-cancer Therapy. Curr Top Med Chem 2010.
20. Rodriguez-Berriguete G, Fraile B, de Bethencourt FR, et al. Roleof IAPs in prostate cancer progression: immunohistochemical studyin normal and pathological (benign hyperplastic, prostaticintraepithelial neoplasia and cancer) human prostate. BMC Cancer 2010; 10: 18.
21. Salvesen GS, Duckett CS. IAP proteins: blocking the road todeath's door. Nat Rev Mol Cell Biol 2002; 3: 401-10.
22. Eckelman BP, Salvesen GS, Scott FL. Human inhibitor ofapoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep 2006; 7: 988-94.
23. Srinivasula SM, Ashwell JD. IAPs: what's in a name? Mol Cell 2008; 30: 123-35.
24. Gyrd-Hansen M, Meier P. IAPs: from caspase inhibitors tomodulators of NF-kappaB, inflammation and cancer. Nat RevCancer 2010; 10: 561-74.
25. Van Camp G, Coucke P, Speleman F, et al. The gene for humangap junction protein connexin37 (GJA4) maps to chromosome1p35.1, in the vicinity of D1S195. Genomics 1995; 30: 402-3.
26. Liston P, Roy N, Tamai K, et al. Suppression of apoptosis inmammalian cells by NAIP and a related family of IAP genes. Nature 1996; 379: 349-53.
27. Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV. TheTNFR2-TRAF signaling complex contains two novel proteinsrelated to baculoviral inhibitor of apoptosis proteins. Cell 1995; 83:1243-52.
28. Uren AG, Pakusch M, Hawkins CJ, Puls KL, Vaux DL. Cloningand expression of apoptosis inhibitory protein homologs thatfunction to inhibit apoptosis and/or bind tumor necrosis factorreceptor-associated factors. Proc Natl Acad Sci USA 1996; 93:4974-8.
29. Duckett CS, Nava VE, Gedrich RW, et al. A conserved family ofcellular genes related to the baculovirus iap gene and encodingapoptosis inhibitors. EMBO J 1996; 15: 2685-94.
30. Lagace M, Xuan JY, Young SS, et al. Genomic organization of theX-linked inhibitor of apoptosis and identification of a novel testisspecifictranscript. Genomics 2001; 77: 181-8.
31. Hauser HP, Bardroff M, Pyrowolakis G, Jentsch S. A giantubiquitin-conjugating enzyme related to IAP apoptosis inhibitors. JCell Biol 1998; 141: 1415-22.
32. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene,survivin, expressed in cancer and lymphoma. Nat Med 1997; 3:917-21.
33. Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit VM.ML-IAP, a novel inhibitor of apoptosis that is preferentiallyexpressed in human melanomas. Curr Biol 2000; 10: 1359-66.
34. Hinds MG, Norton RS, Vaux DL, Day CL. Solution structure of abaculoviral inhibitor of apoptosis (IAP) repeat. Nat Struct Biol 1999; 6: 648-51.
35. Sun C, Cai M, Gunasekera AH, et al. NMR structure andmutagenesis of the inhibitor-of-apoptosis protein XIAP. Nature 1999; 401: 818-22.
36. Altieri DC. Survivin and IAP proteins in cell-death mechanisms. Biochem J 2010; 430: 199-205.
37. Yang Y, Fang S, Jensen JP, Weissman AM, Ashwell JD. Ubiquitinprotein ligase activity of IAPs and their degradation in proteasomesin response to apoptotic stimuli. Science 2000; 288: 874-7.
38. Suzuki Y, Nakabayashi Y, Takahashi R. Ubiquitin-protein ligaseactivity of X-linked inhibitor of apoptosis protein promotesproteasomal degradation of caspase-3 and enhances its antiapoptoticeffect in Fas-induced cell death. Proc Natl Acad Sci USA 2001; 98: 8662-7.
39. Martin SJ. Dealing the CARDs between life and death. Trends CellBiol 2001; 11: 188-9.
40. Plenchette S, Cathelin S, Rebe C, et al. Translocation of theinhibitor of apoptosis protein c-IAP1 from the nucleus to the Golgiin hematopoietic cells undergoing differentiation: a nuclear exportsignal-mediated event. Blood 2004; 104: 2035-43.
41. Verdecia MA, Huang H, Dutil E, Kaiser DA, Hunter T, Noel JP. Structure of the human anti-apoptotic protein survivin reveals adimeric arrangement. Nat Struct Biol 2000; 7: 602-8.
42. Lu B, Mu Y, Cao C, et al. Survivin as a therapeutic target forradiation sensitization in lung cancer. Cancer Res 2004; 64: 2840-5.
43. Chandele A, Prasad V, Jagtap JC, Shukla R, Shastry PR.Upregulation of survivin in G2/M cells and inhibition of caspase 9activity enhances resistance in staurosporine-induced apoptosis. Neoplasia 2004; 6: 29-40.
44. Li F, Ambrosini G, Chu EY, et al. Control of apoptosis and mitoticspindle checkpoint by survivin. Nature 1998; 396: 580-4.
45. Yamamoto H, Ngan CY, Monden M. Cancer cells survive withsurvivin. Cancer Sci 2008; 99: 1709-14.
46. Tamm I, Wang Y, Sausville E, et al. IAP-family protein survivininhibits caspase activity and apoptosis induced by Fas (CD95),Bax, caspases, and anticancer drugs. Cancer Res 1998; 58: 5315-20.
47. Shin S, Sung BJ, Cho YS, et al. An anti-apoptotic protein humansurvivin is a direct inhibitor of caspase-3 and -7. Biochemistry 2001; 40: 1117-23.
48. Sun C, Nettesheim D, Liu Z, Olejniczak ET. Solution structure ofhuman survivin and its binding interface with Smac/Diablo. Biochemistry 2005; 44: 11-7.
49. Ceballos-Cancino G, Espinosa M, Maldonado V, Melendez-ZajglaJ. Regulation of mitochondrial Smac/DIABLO-selective release bysurvivin. Oncogene 2007; 26: 7569-75.
50. Yang D, Welm A, Bishop JM. Cell division and cell survival in theabsence of survivin. Proc Natl Acad Sci USA 2004; 101: 15100-5.
51. Lens SM, Wolthuis RM, Klompmaker R, et al. Survivin is requiredfor a sustained spindle checkpoint arrest in response to lack oftension. EMBO J 2003; 22: 2934-47.
52. Altieri DC. Validating survivin as a cancer therapeutic target. NatRev Cancer 2003; 3: 46-54.
53. Badran A, Yoshida A, Ishikawa K, et al. Identification of a novelsplice variant of the human anti-apoptopsis gene survivin. BiochemBiophys Res Commun 2004; 314: 902-7.
54. Caldas H, Honsey LE, Altura RA. Survivin 2alpha: a novelSurvivin splice variant expressed in human malignancies. MolCancer 2005; 4: 11.
55. Conway EM, Pollefeyt S, Cornelissen J, et al. Three differentiallyexpressed survivin cDNA variants encode proteins with distinctantiapoptotic functions. Blood 2000; 95: 1435-42.
56. Mahotka C, Wenzel M, Springer E, Gabbert HE, Gerharz CD.Survivin-deltaEx3 and survivin-2B: two novel splice variants of theapoptosis inhibitor survivin with different antiapoptotic properties. Cancer Res 1999; 59: 6097-102.
57. Zhao J, Tenev T, Martins LM, Downward J, Lemoine NR. Theubiquitin-proteasome pathway regulates survivin degradation in acell cycle-dependent manner. J Cell Sci 2000; 113 Pt 23: 4363-71.
58. Kim PJ, Plescia J, Clevers H, Fearon ER, Altieri DC. Survivin andmolecular pathogenesis of colorectal cancer. Lancet 2003; 362:205-9.
59. Li F, Altieri DC. Transcriptional analysis of human survivin geneexpression. Biochem J 1999; 344 Pt 2: 305-11.
60. Ngan CY, Yamamoto H, Takagi A, et al. Oxaliplatin inducesmitotic catastrophe and apoptosis in esophageal cancer cells. Cancer Sci 2008; 99: 129-39.
61. Gritsko T, Williams A, Turkson J, et al. Persistent activation ofstat3 signaling induces survivin gene expression and confersresistance to apoptosis in human breast cancer cells. Clin CancerRes 2006; 12: 11-9.
62. Chang E, Donahue J, Smith A, et al. Loss of p53, rather than betacateninoverexpression, induces survivin-mediated resistance toapoptosis in an esophageal cancer cell line. J Thorac CardiovascSurg 2010; 140: 225-32.
63. Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR, Katzenellenbogen BS. Profiling of estrogen up- and downregulatedgene expression in human breast cancer cells: insightsinto gene networks and pathways underlying estrogenic control ofproliferation and cell phenotype. Endocrinology 2003; 144: 4562-74.
64. O'Connor DS, Grossman D, Plescia J, et al. Regulation of apoptosisat cell division by p34cdc2 phosphorylation of survivin. Proc NatlAcad Sci USA 2000; 97: 13103-7.
65. Green DR. Apoptotic pathways: the roads to ruin. Cell 1998; 94:695-8.
66. Suzuki A, Ito T, Kawano H, et al. Survivin initiates procaspase3/p21 complex formation as a result of interaction with Cdk4 toresist Fas-mediated cell death. Oncogene 2000; 19: 1346-53.
67. Blanc-Brude OP, Mesri M, Wall NR, Plescia J, Dohi T, Altieri DC.Therapeutic targeting of the survivin pathway in cancer: initiationof mitochondrial apoptosis and suppression of tumor-associatedangiogenesis. Clin Cancer Res 2003; 9: 2683-92.
68. Bright SA, Campiani G, Deininger MW, Lawler M, Williams DC, Zisterer DM. Sequential treatment with flavopiridol synergisticallyenhances pyrrolo-1,5-benzoxazepine-induced apoptosis in humanchronic myeloid leukaemia cells including those resistant toimatinib treatment. Biochem Pharmacol 2010; 80: 31-8.
69. Cho SJ, Lee SS, Kim YJ, et al. Xylocydine, a novel Cdk inhibitor,is an effective inducer of apoptosis in hepatocellular carcinomacells in vitro and in vivo. Cancer Lett 2010; 287: 196-206.
70. Shapiro GI. Preclinical and clinical development of the cyclindependentkinase inhibitor flavopiridol. Clin Cancer Res 2004; 10:4270s-4275s.
71. Whittaker SR, Walton MI, Garrett MD, Workman P. The Cyclindependentkinase inhibitor CYC202 (R-roscovitine) inhibitsretinoblastoma protein phosphorylation, causes loss of Cyclin D1,and activates the mitogen-activated protein kinase pathway. CancerRes 2004; 64: 262-72.
72. De Azevedo WF, Leclerc S, Meijer L, Havlicek L, Strnad M, Kim SH. Inhibition of cyclin-dependent kinases by purine analogues:crystal structure of human cdk2 complexed with roscovitine. Eur JBiochem 1997; 243: 518-26.
73. Alessi F, Quarta S, Savio M, et al. The cyclin-dependent kinaseinhibitors olomoucine and roscovitine arrest human fibroblasts inG1 phase by specific inhibition of CDK2 kinase activity. Exp CellRes 1998; 245: 8-18.
74. Meijer L, Borgne A, Mulner O, et al. Biochemical and cellulareffects of roscovitine, a potent and selective inhibitor of the cyclindependentkinases cdc2, cdk2 and cdk5. Eur J Biochem 1997; 243:527-36.
75. Wesierska-Gadek J, Borza A, Walzi E, et al. Outcome of treatmentof human HeLa cervical cancer cells with roscovitine stronglydepends on the dosage and cell cycle status prior to the treatment. JCell Biochem 2009; 106: 937-55.
76. Coley HM, Shotton CF, Thomas H. Seliciclib (CYC202; rroscovitine)in combination with cytotoxic agents in human uterinesarcoma cell lines. Anticancer Res 2007; 27: 273-8.
77. Tirado OM, Mateo-Lozano S, Notario V. Roscovitine is aneffective inducer of apoptosis of Ewing's sarcoma family tumorcells in vitro and in vivo. Cancer Res 2005; 65: 9320-7.
78. O'Connor DS, Wall NR, Porter AC, Altieri DC. A p34(cdc2)survival checkpoint in cancer. Cancer Cell 2002; 2: 43-54.
79. Wall NR, O'Connor DS, Plescia J, Pommier Y, Altieri DC.Suppression of survivin phosphorylation on Thr34 by flavopiridolenhances tumor cell apoptosis. Cancer Res 2003; 63: 230-5.
80. DeGregori J, Johnson DG. Distinct and Overlapping Roles for E2FFamily Members in Transcription, Proliferation and Apoptosis. Curr Mol Med 2006; 6: 739-48.
81. Dimova DK, Dyson NJ. The E2F transcriptional network: oldacquaintances with new faces. Oncogene 2005; 24: 2810-26.
82. Polager S, Ginsberg D. E2F - at the crossroads of life and death.Trends Cell Biol 2008; 18: 528-35.
83. Polager S, Ginsberg D. p53 and E2f: partners in life and death. NatRev Cancer 2009; 9: 738-48.
84. Ren B, Cam H, Takahashi Y, et al. E2F integrates cell cycleprogression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev 2002; 16: 245-56.
85. Cam H, Balciunaite E, Blais A, et al. A common set of generegulatory networks links metabolism and growth inhibition. MolCell 2004; 16: 399-411.
86. Bracken AP, Ciro M, Cocito A, Helin K. E2F target genes:unraveling the biology. Trends Biochem Sci 2004; 29: 409-17.
87. Johnson DG, Cress WD, Jakoi L, Nevins JR. Oncogenic capacityof the E2F1 gene. Proc Natl Acad Sci USA 1994; 91: 12823-7.
88. Pierce AM, Schneider-Broussard R, Gimenez-Conti IB, Russell JL, Conti CJ, Johnson DG. E2F1 has both oncogenic and tumorsuppressiveproperties in a transgenic model. Mol Cell Biol 1999;19: 6408-14.
89. Field SJ, Tsai FY, Kuo F, et al. E2F-1 functions in mice to promoteapoptosis and suppress proliferation. Cell 1996; 85: 549-61.
90. Yamasaki L, Jacks T, Bronson R, Goillot E, Harlow E, Dyson NJ.Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 1996; 85: 537-48.
91. Stevens C, La Thangue NB. E2F and cell cycle control: a doubleedgedsword. Arch Biochem Biophys 2003; 412: 157-69.
92. Shapiro GI. Cyclin-dependent kinase pathways as targets for cancertreatment. J Clin Oncol 2006; 24: 1770-83.
93. Ma Y, Cress WD, Haura EB. Flavopiridol-induced apoptosis ismediated through up-regulation of E2F1 and repression of Mcl-1. Mol Cancer Ther 2003; 2: 73-81.
94. Bates S, Phillips AC, Clark PA, et al. p14ARF links the tumoursuppressors RB and p53. Nature 1998; 395: 124-5.
95. Fogal V, Hsieh JK, Royer C, Zhong S, Lu X. Cell cycle-dependentnuclear retention of p53 by E2F1 requires phosphorylation of p53at Ser315. EMBO J 2005; 24: 2768-82.
96. Hsieh JK, Yap D, O'Connor DJ, et al. Novel function of the cyclinA binding site of E2F in regulating p53-induced apoptosis inresponse to DNA damage. Mol Cell Biol 2002; 22: 78-93.
97. Ryo A, Liou YC, Wulf G, Nakamura M, Lee SW, Lu KP. PIN1 isan E2F target gene essential for Neu/Ras-induced transformation ofmammary epithelial cells. Mol Cell Biol 2002; 22: 5281-95.
98. Zacchi P, Gostissa M, Uchida T, et al. The prolyl isomerase Pin1reveals a mechanism to control p53 functions after genotoxicinsults. Nature 2002; 419: 853-7.
99. Croxton R, Ma Y, Song L, Haura EB, Cress WD. Direct repressionof the Mcl-1 promoter by E2F1. Oncogene 2002; 21: 1359-69.
100. Gomez-Gutierrez JG, Garcia-Garcia A, Hao H, et al. Adenovirusmediatedexpression of truncated E2F-1 suppresses tumor growthin vitro and in vivo. Cancer 2010; 116: 4420-32.
101. Ortiz-Ferron G, Yerbes R, Eramo A, Lopez-Perez AI, De Maria R, Lopez-Rivas A. Roscovitine sensitizes breast cancer cells toTRAIL-induced apoptosis through a pleiotropic mechanism. CellRes 2008; 18: 664-76.
102. Jiang J, Matranga CB, Cai D, et al. Flavopiridol-induced apoptosisduring S phase requires E2F-1 and inhibition of cyclin Adependentkinase activity. Cancer Res 2003; 63: 7410-22.
103. Dong YB, Yang HL, Elliott MJ, McMasters KM. AdenovirusmediatedE2F-1 gene transfer sensitizes melanoma cells toapoptosis induced by topoisomerase II inhibitors. Cancer Res 2002;62: 1776-83.
104. Chen YN, Sharma SK, Ramsey TM, et al. Selective killing oftransformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc Natl Acad Sci USA 1999; 96: 4325-9.
105. Danial NN. BAD: undertaker by night, candyman by day. Oncogene 2008; 27 Suppl 1: S53-70.
106. Zhang HM, Cheung P, Yanagawa B, McManus BM, Yang DC. BNips: a group of pro-apoptotic proteins in the Bcl-2 family. Apoptosis 2003; 8: 229-36.
107. Harada H, Becknell B, Wilm M, et al. Phosphorylation andinactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell 1999; 3: 413-22.
108. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell 2004; 116: 205-19.
109. Youle RJ, Strasser A. The BCL-2 protein family: opposingactivities that mediate cell death. Nat Rev Mol Cell Biol 2008; 9:47-59.
110. Cheng EH, Wei MC, Weiler S, et al. BCL-2, BCL-X(L) sequesterBH3 domain-only molecules preventing BAX- and BAK-mediatedmitochondrial apoptosis. Mol Cell 2001; 8: 705-11.
111. Wei MC, Zong WX, Cheng EH, et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 2001; 292: 727-30.
112. Bergmann A. Survival signaling goes BAD. Dev Cell 2002; 3: 607-8.
113. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BADcouples survival signals to the cell-intrinsic death machinery. Cell 1997; 91: 231-41.
114. Yu C, Rahmani M, Dai Y, et al. The lethal effects ofpharmacological cyclin-dependent kinase inhibitors in humanleukemia cells proceed through a phosphatidylinositol 3-kinase/Akt-dependent process. Cancer Res 2003; 63: 1822-33.
115. Jiang P, Du W, Heese K, Wu M. The Bad guy cooperates withgood cop p53: Bad is transcriptionally up-regulated by p53 andforms a Bad/p53 complex at the mitochondria to induce apoptosis. Mol Cell Biol 2006; 26: 9071-82.
116. Wesierska-Gadek J, Wandl S, Kramer MP, Pickem C, Krystof V,Hajek SB. Roscovitine up-regulates p53 protein and inducesapoptosis in human HeLaS(3) cervix carcinoma cells. J CellBiochem 2008; 105: 1161-71.
117. Wesierska-Gadek J, Schmitz ML, Ranftler C. RoscovitineactivatedHIP2 kinase induces phosphorylation of wt p53 at Ser-46in human MCF-7 breast cancer cells. J Cell Biochem 2007; 100:865-74.
118. Krystof V, McNae IW, Walkinshaw MD, et al. Antiproliferativeactivity of olomoucine II, a novel 2,6,9-trisubstituted purine cyclindependentkinase inhibitor. Cell Mol Life Sci 2005; 62: 1763-71.
119. Mohapatra S, Chu B, Zhao X, Pledger WJ. Accumulation of p53and reductions in XIAP abundance promote the apoptosis ofprostate cancer cells. Cancer Res 2005; 65: 7717-23.
120. Fesquet D, Labbe JC, Derancourt J, et al. The MO15 gene encodesthe catalytic subunit of a protein kinase that activates cdc2 andother cyclin-dependent kinases (CDKs) through phosphorylation ofThr161 and its homologues. EMBO J 1993; 12: 3111-21.
121. Poon RY, Yamashita K, Adamczewski JP, Hunt T, Shuttleworth J.The cdc2-related protein p40MO15 is the catalytic subunit of aprotein kinase that can activate p33cdk2 and p34cdc2. EMBO J 1993; 12: 3123-32.
122. Solomon MJ, Harper JW, Shuttleworth J. CAK, the p34cdc2activating kinase, contains a protein identical or closely related top40MO15. EMBO J 1993; 12: 3133-42.
123. Devault A, Martinez AM, Fesquet D, et al. MAT1 ('menage atrois') a new RING finger protein subunit stabilizing cyclin H-cdk7complexes in starfish and Xenopus CAK. EMBO J 1995; 14: 5027-36.
124. Larochelle S, Chen J, Knights R, et al. T-loop phosphorylationstabilizes the CDK7-cyclin H-MAT1 complex in vivo and regulatesits CTD kinase activity. EMBO J 2001; 20: 3749-59.
125. Larochelle S, Merrick KA, Terret ME, et al. Requirements forCdk7 in the assembly of Cdk1/cyclin B and activation of Cdk2revealed by chemical genetics in human cells. Mol Cell 2007; 25:839-50.
126. Rossi DJ, Londesborough A, Korsisaari N, et al. Inability to enter Sphase and defective RNA polymerase II CTD phosphorylation inmice lacking Mat1. EMBO J 2001; 20: 2844-56.
127. Schneider E, Kartarius S, Schuster N, Montenarh M. The cyclinH/cdk7/Mat1 kinase activity is regulated by CK2 phosphorylationof cyclin H. Oncogene 2002; 21: 5031-7.
128. Grana X, De Luca A, Sang N, et al. PITALRE, a nuclear CDC2-related protein kinase that phosphorylates the retinoblastomaprotein in vitro. Proc Natl Acad Sci USA 1994; 91: 3834-8.
129. Garriga J, Grana X. Cellular control of gene expression by T-typecyclin/CDK9 complexes. Gene 2004; 337: 15-23.
130. Giacinti C, Musaro A, De Falco G, et al. Cdk9-55: a new player inmuscle regeneration. J Cell Physiol 2008; 216: 576-82.
131. Canduri F, Perez PC, Caceres RA, de Azevedo WF, Jr. CDK9 apotential target for drug development. Med Chem 2008; 4: 210-8.
132. Li Q, Price JP, Byers SA, Cheng D, Peng J, Price DH. Analysis ofthe large inactive P-TEFb complex indicates that it contains one7SK molecule, a dimer of HEXIM1 or HEXIM2, and two P-TEFbmolecules containing Cdk9 phosphorylated at threonine 186. J BiolChem 2005; 280: 28819-26.
133. Garber ME, Mayall TP, Suess EM, Meisenhelder J, Thompson NE,Jones KA. CDK9 autophosphorylation regulates high-affinitybinding of the human immunodeficiency virus type 1 tat-P-TEFbcomplex to TAR RNA. Mol Cell Biol 2000; 20: 6958-69.
134. Marshall RM, Grana X. Mechanisms controlling CDK9 activity. Front Biosci 2006; 11: 2598-613.
135. Schulte A, Czudnochowski N, Barboric M, et al. Identification of acyclin T-binding domain in Hexim1 and biochemical analysis of itsbinding competition with HIV-1 Tat. J Biol Chem 2005; 280:24968-77.
136. Bisgrove DA, Mahmoudi T, Henklein P, Verdin E. Conserved PTEFb-interacting domain of BRD4 inhibits HIV transcription. ProcNatl Acad Sci USA 2007; 104: 13690-5.
137. Zhou M, Nekhai S, Bharucha DC, et al. TFIIH inhibits CDK9phosphorylation during human immunodeficiency virus type 1transcription. J Biol Chem 2001; 276: 44633-40.
138. Core LJ, Lis JT. Transcription regulation through promoterproximalpausing of RNA polymerase II. Science 2008; 319: 1791-2.
139. Bres V, Yoh SM, Jones KA. The multi-tasking P-TEFb complex. Curr Opin Cell Biol 2008; 20: 334-40.
140. De Falco G, Leucci E, Onnis A, et al. Cdk9/Cyclin T1 complex: akey player during the activation/differentiation process of normallymphoid B cells. J Cell Physiol 2008; 215: 276-82.
141. Foskett SM, Ghose R, Tang DN, Lewis DE, Rice AP. Antiapoptotic function of Cdk9 (TAK/P-TEFb) in U937promonocytic cells. J Virol 2001; 75: 1220-8.
142. De Falco G, Giordano A. CDK9: from basal transcription to cancerand AIDS. Cancer Biol Ther 2002; 1: 342-7.
143. Romano G, Giordano A. Role of the cyclin-dependent kinase 9-related pathway in mammalian gene expression and humandiseases. Cell Cycle 2008; 7: 3664-8.
144. Wang S, Fischer PM. Cyclin-dependent kinase 9: a keytranscriptional regulator and potential drug target in oncology,virology and cardiology. Trends Pharmacol Sci 2008; 29: 302-13.
145. Nechaev S, Adelman K. Promoter-proximal Pol II: when stallingspeeds things up. Cell Cycle 2008; 7: 1539-44.
146. Buratowski S. The CTD code. Nat Struct Biol 2003; 10: 679-80.
147. Komarnitsky P, Cho EJ, Buratowski S. Different phosphorylatedforms of RNA polymerase II and associated mRNA processingfactors during transcription. Genes Dev 2000; 14: 2452-60.
148. Fabrega C, Shen V, Shuman S, Lima CD. Structure of an mRNAcapping enzyme bound to the phosphorylated carboxy-terminaldomain of RNA polymerase II. Mol Cell 2003; 11: 1549-61.
149. Muse GW, Gilchrist DA, Nechaev S, Shah R, Parker JS, Grissom SF, et al. RNA polymerase is poised for activation across thegenome. Nat Genet 2007; 39: 1507-11.
150. Zeitlinger J, Stark A, Kellis M, et al. RNA polymerase stalling atdevelopmental control genes in the Drosophila melanogasterembryo. Nat Genet 2007; 39: 1512-6.
151. Wada T, Takagi T, Yamaguchi Y, Watanabe D, Handa H.Evidence that P-TEFb alleviates the negative effect of DSIF onRNA polymerase II-dependent transcription in vitro. EMBO J 1998; 17: 7395-403.
152. Renner DB, Yamaguchi Y, Wada T, Handa H, Price DH. A highlypurified RNA polymerase II elongation control system. J BiolChem 2001; 276: 42601-9.
153. Peterlin BM, Price DH. Controlling the elongation phase oftranscription with P-TEFb. Mol Cell 2006; 23: 297-305.
154. Saunders A, Core LJ, Lis JT. Breaking barriers to transcriptionelongation. Nat Rev Mol Cell Biol 2006; 7: 557-67.
155. Paprskarova M, Krystof V, Jorda R, et al. Functional p53 in cellscontributes to the anticancer effect of the cyclin-dependent kinaseinhibitor roscovitine. J Cell Biochem 2009; 107: 428-37.
156. Senderowicz AM, Headlee D, Stinson SF, Lush RM, Kalil N, Villalba L, et al. Phase I trial of continuous infusion flavopiridol, anovel cyclin-dependent kinase inhibitor, in patients with refractoryneoplasms. J Clin Oncol 1998; 16: 2986-99.
157. Sedlacek HH, Czech J, Naik R, et al. Flavopiridol (L86 8275; NSC649890), a new kinase inhibitor for tumor therapy. InternationalJournal of Oncology 1996; 9: 1143-1168.
158. Blagosklonny MV. Flavopiridol, an inhibitor of transcription:implications, problems and solutions. Cell Cycle 2004; 3: 1537-42.
159. Chao SH, Fujinaga K, Marion JE, et al. Flavopiridol inhibits PTEFband blocks HIV-1 replication. J Biol Chem 2000; 275:28345-8.
160. Chao SH, Price DH. Flavopiridol inactivates P-TEFb and blocksmost RNA polymerase II transcription in vivo. J Biol Chem 2001;276: 31793-9.
161. Shima D, Yugami M, Tatsuno M, Wada T, Yamaguchi Y, HandaH. Mechanism of H-8 inhibition of cyclin-dependent kinase 9:study using inhibitor-immobilized matrices. Genes Cells 2003; 8:215-23.
162. Raynaud FI, Whittaker SR, Fischer PM, et al. In vitro and in vivopharmacokinetic-pharmacodynamic relationships for thetrisubstituted aminopurine cyclin-dependent kinase inhibitorsolomoucine, bohemine and CYC202. Clin Cancer Res 2005; 11:4875-87.
163. Wesierska-Gadek J, Walzi E, Doleckova I, Schmid G. Oncogenesdo not Fully Override Cell-intrinsic Traits: Pronounced Impact ofthe Cellular Programme. Cancer Microenviron 2009.
164. Wesierska-Gadek J, Hackl S, Zulehner N, Maurer M, Komina O.Reconstitution of human MCF-7 breast cancer cells with caspase-3does not sensitize them to action of CDK inhibitors. J CellBiochem 2010.
165. Conroy A, Stockett DE, Walker D, et al. SNS-032 is a potent andselective CDK 2, 7 and 9 inhibitor that drives target modulation inpatient samples. Cancer Chemother Pharmacol 2009; 64: 723-32.
166. Heath EI, Bible K, Martell RE, Adelman DC, Lorusso PM. A phase1 study of SNS-032 (formerly BMS-387032), a potent inhibitor ofcyclin-dependent kinases 2, 7 and 9 administered as a single oraldose and weekly infusion in patients with metastatic refractorysolid tumors. Invest New Drugs 2008; 26: 59-65.
167. Ali S, Heathcote DA, Kroll SH, et al. The development of aselective cyclin-dependent kinase inhibitor that shows antitumoractivity. Cancer Res 2009; 69: 6208-15.
168. Wang S, Midgley CA, Scaerou F, et al. Discovery of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors. J MedChem 2010; 53: 4367-78.
169. Krystof V, Cankar P, Frysova I, et al. 4-arylazo-3,5-diamino-1HpyrazoleCDK inhibitors: SAR study, crystal structure in complexwith CDK2, selectivity, and cellular effects. J Med Chem 2006; 49:6500-9.
170. Heuer T. Discovery of selective CDK9 small molecule inhibitors:CDK9 inhibition in tumor cells is associated with inhibition ofproliferation and induction of apoptosis. Ejc Supplements 2008; 6:94-94.
171. Krystof V, Lenobel R, Havlicek L, Kuzma M, Strnad M. Synthesisand biological activity of olomoucine II. Bioorg Med Chem Lett 2002; 12: 3283-6.
172. Nemeth G, Varga Z, Greff Z, et al. Novel, Selective CDK9Inhibitors for the Treatment of HIV Infection. Curr Med Chem 2010.
173. Wesierska-Gadek J, Borza A, Komina O, Maurer M. Impact ofroscovitine, a selective CDK inhibitor, on cancer cells: bifunctionalityincreases its therapeutic potential. Acta Biochim Pol 2009; 56: 495-501.
174. Rosato RR, Almenara JA, Kolla SS, et al. Mechanism andfunctional role of XIAP and Mcl-1 down-regulation inflavopiridol/vorinostat antileukemic interactions. Mol Cancer Ther 2007; 6: 692-702.
175. Whittaker SR, Te Poele RH, Chan F, et al. The cyclin-dependentkinase inhibitor seliciclib (R-roscovitine; CYC202) decreases theexpression of mitotic control genes and prevents entry into mitosis. Cell Cycle 2007; 6: 3114-31.
176. Wesierska-Gadek J, Gueorguieva M, Horky M. Roscovitineinducedup-regulation of p53AIP1 protein precedes the onset ofapoptosis in human MCF-7 breast cancer cells. Mol Cancer Ther 2005; 4: 113-24.
177. Dey A, Wong ET, Cheok CF, Tergaonkar V, Lane DP. RRoscovitinesimultaneously targets both the p53 and NF-kappaBpathways and causes potentiation of apoptosis: implications incancer therapy. Cell Death Differ 2008; 15: 263-73.
178. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis - the p53network. J Cell Sci 2003; 116: 4077-85.
179. Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M. Wild-type p53 induces apoptosis of myeloid leukaemic cellsthat is inhibited by interleukin-6. Nature 1991; 352: 345-7.
180. Cregan SP, MacLaurin JG, Craig CG, et al. Bax-dependentcaspase-3 activation is a key determinant in p53-induced apoptosisin neurons. J Neurosci 1999; 19: 7860-9.
181. Slack RS, Belliveau DJ, Rosenberg M, et al. Adenovirus-mediatedgene transfer of the tumor suppressor, p53, induces apoptosis inpostmitotic neurons. J Cell Biol 1996; 135: 1085-96.
182. Xu X, Yang D, Wyss-Coray T, et al. Wild-type but not Alzheimermutantamyloid precursor protein confers resistance against p53-mediated apoptosis. Proc Natl Acad Sci USA 1999; 96: 7547-52.
183. Bellamy CO, Clarke AR, Wyllie AH, Harrison DJ. p53 Deficiencyin liver reduces local control of survival and proliferation, but doesnot affect apoptosis after DNA damage. Faseb J 1997; 11: 591-9.
184. Crumrine RC, Thomas AL, Morgan PF. Attenuation of p53expression protects against focal ischemic damage in transgenicmice. J Cereb Blood Flow Metab 1994; 14: 887-91.
185. Morrison RS, Wenzel HJ, Kinoshita Y, Robbins CA, Donehower LA, Schwartzkroin PA. Loss of the p53 tumor suppressor geneprotects neurons from kainate-induced cell death. J Neurosci 1996;16: 1337-45.
186. Laptenko O, Prives C. Transcriptional regulation by p53: oneprotein, many possibilities. Cell Death Differ 2006; 13: 951-61.
187. Fritsche M, Haessler C, Brandner G. Induction of nuclearaccumulation of the tumor-suppressor protein p53 by DNAdamagingagents. Oncogene 1993; 8: 307-18.
188. Maltzman W, Czyzyk L. UV irradiation stimulates levels of p53cellular tumor antigen in nontransformed mouse cells. Mol CellBiol 1984; 4: 1689-94.
189. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapiddegradation of p53. Nature 1997; 387: 296-9.
190. Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stabilityby Mdm2. Nature 1997; 387: 299-303.
191. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. Themdm-2 oncogene product forms a complex with the p53 proteinand inhibits p53-mediated transactivation. Cell 1992; 69: 1237-45.
192. Wojciechowski J, Horky M, Gueorguieva M, Wesierska-Gadek J.Rapid onset of nucleolar disintegration preceding cell cycle arrestin roscovitine-induced apoptosis of human MCF-7 breast cancercells. Int J Cancer 2003; 106: 486-95.
193. Blagosklonny MV. P53: an ubiquitous target of anticancer drugs. Int J Cancer 2002; 98: 161-6.
194. Oda K, Arakawa H, Tanaka T, et al. p53AIP1, a potential mediatorof p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 2000; 102: 849-62.
195. Matsuda K, Yoshida K, Taya Y, Nakamura K, Nakamura Y, Arakawa H. p53AIP1 regulates the mitochondrial apoptoticpathway. Cancer Res 2002; 62: 2883-9.
196. Oda E, Ohki R, Murasawa H, et al. Noxa, a BH3-only member ofthe Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000; 288: 1053-8.
197. Yoshida K, Monden M, Nakamura Y, Arakawa H. Adenovirusmediatedp53AIP1 gene transfer as a new strategy for treatment ofp53-resistant tumors. Cancer Sci 2004; 95: 91-7.
198. Attardi LD, Reczek EE, Cosmas C, Demicco EG, McCurrach ME, Lowe SW, et al. PERP, an apoptosis-associated target of p53, is anovel member of the PMP-22/gas3 family. Genes Dev 2000; 14:704-18.
199. Koumenis C, Alarcon R, Hammond E, et al. Regulation of p53 byhypoxia: dissociation of transcriptional repression and apoptosisfrom p53-dependent transactivation. Mol Cell Biol 2001; 21: 1297-310.
200. Nakade K, Zheng H, Ganguli G, Buchwalter G, Gross C, WasylykB. The tumor suppressor p53 inhibits Net, an effector ofRas/extracellular signal-regulated kinase signaling. Mol Cell Biol 2004; 24: 1132-42.
201. Seto E, Usheva A, Zambetti GP, et al. Wild-type p53 binds to theTATA-binding protein and represses transcription. Proc Natl Acad Sci USA 1992; 89: 12028-32.
202. Miyashita T, Harigai M, Hanada M, Reed JC. Identification of ap53-dependent negative response element in the bcl-2 gene. CancerRes 1994; 54: 3131-5.
203. Cregan SP, Arbour NA, Maclaurin JG, et al. p53 activation domain1 is essential for PUMA upregulation and p53-mediated neuronalcell death. J Neurosci 2004; 24: 10003-12.
204. Zhu J, Zhang S, Jiang J, Chen X. Definition of the p53 functionaldomains necessary for inducing apoptosis. J Biol Chem 2000; 275:39927-34.
205. Huang DC, Strasser A. BH3-Only proteins-essential initiators ofapoptotic cell death. Cell 2000; 103: 839-42.
206. Puthalakath H, Strasser A. Keeping killers on a tight leash:transcriptional and post-translational control of the pro-apoptoticactivity of BH3-only proteins. Cell Death Differ 2002; 9: 505-12.
207. Melino G, Bernassola F, Ranalli M, et al. p73 Induces apoptosisvia PUMA transactivation and Bax mitochondrial translocation. JBiol Chem 2004; 279: 8076-83.
208. Hershko T, Ginsberg D. Up-regulation of Bcl-2 homology 3(BH3)-only proteins by E2F1 mediates apoptosis. J Biol Chem 2004; 279: 8627-34.
209. Bonini P, Cicconi S, Cardinale A, et al. Oxidative stress inducesp53-mediated apoptosis in glia: p53 transcription-independent wayto die. J Neurosci Res 2004; 75: 83-95.
210. Caelles C, Helmberg A, Karin M. p53-dependent apoptosis in theabsence of transcriptional activation of p53-target genes. Nature 1994; 370: 220-3.
211. Haupt Y, Rowan S, Shaulian E, Vousden KH, Oren M. Inductionof apoptosis in HeLa cells by trans-activation-deficient p53. GenesDev 1995; 9: 2170-83.
212. Charlot JF, Pretet JL, Haughey C, Mougin C. Mitochondrialtranslocation of p53 and mitochondrial membrane potential (DeltaPsi m) dissipation are early events in staurosporine-inducedapoptosis of wild type and mutated p53 epithelial cells. Apoptosis 2004; 9: 333-43.
213. Chipuk JE, Maurer U, Green DR, Schuler M. Pharmacologicactivation of p53 elicits Bax-dependent apoptosis in the absence oftranscription. Cancer Cell 2003; 4: 371-81.
214. Mihara M, Erster S, Zaika A, et al. p53 has a direct apoptogenicrole at the mitochondria. Mol Cell 2003; 11: 577-90.
215. Chipuk JE, Kuwana T, Bouchier-Hayes L, et al. Direct activationof Bax by p53 mediates mitochondrial membrane permeabilizationand apoptosis. Science 2004; 303: 1010-4.
216. Marchenko ND, Zaika A, Moll UM. Death signal-inducedlocalization of p53 protein to mitochondria. A potential role inapoptotic signaling. J Biol Chem 2000; 275: 16202-12.
217. Dhariwala FA, Rajadhyaksha MS. An unusual member of the Cdkfamily: Cdk5. Cell Mol Neurobiol 2008; 28: 351-69.
218. Li BS, Sun MK, Zhang L, et al. Regulation of NMDA receptors bycyclin-dependent kinase-5. Proc Natl Acad Sci USA 2001; 98:12742-7.
219. Kim SH, Ryan TA. CDK5 serves as a major control point inneurotransmitter release. Neuron 2010; 67: 797-809.
220. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH. Conversion of p35 to p25 deregulates Cdk5 activity andpromotes neurodegeneration. Nature 1999; 402: 615-22.
221. Poon RY, Lew J, Hunter T. Identification of functional domains inthe neuronal Cdk5 activator protein. J Biol Chem 1997; 272: 5703-8.
222. Patrick GN, Zhou P, Kwon YT, Howley PM, Tsai LH. p35, theneuronal-specific activator of cyclin-dependent kinase 5 (Cdk5) isdegraded by the ubiquitin-proteasome pathway. J Biol Chem 1998;273: 24057-64.
223. Cruz JC, Tsai LH. Cdk5 deregulation in the pathogenesis ofAlzheimer's disease. Trends Mol Med 2004; 10: 452-8.
224. Jessberger S, Gage FH, Eisch AJ, Lagace DC. Making a neuron:Cdk5 in embryonic and adult neurogenesis. Trends Neurosci 2009;32: 575-82.
225. Avraham E, Rott R, Liani E, Szargel R, Engelender S. Phosphorylation of Parkin by the cyclin-dependent kinase 5 at thelinker region modulates its ubiquitin-ligase activity andaggregation. J Biol Chem 2007; 282: 12842-50.
226. Li BS, Zhang L, Takahashi S, et al. Cyclin-dependent kinase 5prevents neuronal apoptosis by negative regulation of c-Jun Nterminalkinase 3. EMBO J 2002; 21: 324-33.
227. Zheng YL, Li BS, Kanungo J, et al. Cdk5 Modulation of mitogenactivatedprotein kinase signaling regulates neuronal survival. MolBiol Cell 2007; 18: 404-13.
228. Li BS, Ma W, Jaffe H, et al. Cyclin-dependent kinase-5 is involvedin neuregulin-dependent activation of phosphatidylinositol 3-kinaseand Akt activity mediating neuronal survival. J Biol Chem 2003;278: 35702-9.
229. Cheung ZH, Gong K, Ip NY. Cyclin-dependent kinase 5 supportsneuronal survival through phosphorylation of Bcl-2. J Neurosci 2008; 28: 4872-7.
230. Lopes JP, Oliveira CR, Agostinho P. Role of cyclin-dependentkinase 5 in the neurodegenerative process triggered by amyloid-Beta and prion peptides: implications for Alzheimer's disease andprion-related encephalopathies. Cell Mol Neurobiol 2007; 27: 943-57.
231. Byrnes KR, Faden AI. Role of cell cycle proteins in CNS injury. Neurochem Res 2007; 32: 1799-807.
232. Gong X, Tang X, Wiedmann M, et al. Cdk5-mediated inhibition ofthe protective effects of transcription factor MEF2 in neurotoxicityinducedapoptosis. Neuron 2003; 38: 33-46.
233. Schmid G, Strosznajder JB, Wesierska-Gadek J. Interplay betweenthe p53 tumor suppressor protein family and Cdk5: noveltherapeutic approaches for the treatment of neurodegenerativediseases using selective Cdk inhibitors. Mol Neurobiol 2006; 34:27-50.
234. Wen Y, Yang S, Liu R, Brun-Zinkernagel AM, Koulen P,Simpkins JW. Transient cerebral ischemia induces aberrantneuronal cell cycle re-entry and Alzheimer's disease-like tauopathyin female rats. J Biol Chem 2004; 279: 22684-92.
235. Hilton GD, Stoica BA, Byrnes KR, Faden AI. Roscovitine reducesneuronal loss, glial activation, and neurologic deficits after braintrauma. J Cereb Blood Flow Metab 2008; 28: 1845-59.
236. Menn B, Bach S, Blevins TL, Campbell M, Meijer L, Timsit S.Delayed treatment with systemic (S)-roscovitine providesneuroprotection and inhibits in vivo CDK5 activity increase inanimal stroke models. PLoS One 2010; 5: e12117.