Which of the following best describes the effect of a drug that blocks the production of the mitotic cyclin?

1. Jacobson MD, Weil M, Raff MC. Programmed cell death in animal development. Cell. 1997;88:347–354. [PubMed] [Google Scholar]

2. Wyllie AH. British Medical Bulletin 53. Dorchester: The Dorset Press; 1997. Apoptosis. [Google Scholar]

3. Golstein P. Controlling cell death. Science. 1997;275:1081–1082. [PubMed] [Google Scholar]

4. King KL, Cidlowsky JA. Cell cycle and apoptosis: common pathways to life and death. J Cell Biochem. 1995;58:175–180. [PubMed] [Google Scholar]

5. Evan GI, Brown L, Whyte M, Harrington E. Apoptosis and the cell cycle. Curr Opin Cell Biol. 1995;7:825–834. [PubMed] [Google Scholar]

6. MacLachlan TK, Sang N, Giordano A. Cyclins, cyclin-dependent kinases and Cdk inhibitors: implications in cell cycle control and cancer. Crit Rev Eukaryotic Gene Expression. 1995;5:127–156. [PubMed] [Google Scholar]

7. Harper JW, Elledge SJ. Cdk inhibitors in development and cancer. Curr Opin Genet Dev. 1996;6:56–84. [PubMed] [Google Scholar]

8. Riley DJ, Lee EY-HP, Lee WH. The retinoblastoma protein: more than a tumor suppressor. Annu Rev Cell Biol. 1994;10:1–29. [PubMed] [Google Scholar]

9. Sidle A, Palaty C, Dirks P, Wiggan O, Kiess M, Gill RM, Wong AK, Hamel PA. Activity of the retinoblastoma family proteins, pRb, p107 and p130, during cellular proliferation and differentiation. Crit Rev Biochem Mol Biol. 1996;31:237–271. [PubMed] [Google Scholar]

10. Weintraub SJ, Chow KN, Luo RX, Zhang SH, He S, Dean DC. Mechanism of active transcriptional repression by the retinoblastoma protein. Nature. 1995;375:812–815. [PubMed] [Google Scholar]

11. Lam EW, La Thangue NB. DP and E2F proteins: coordinating transcription with cell cycle progression. Curr Opin Cell Biol. 1994;6:859–866. [PubMed] [Google Scholar]

12. Amati B, Littlewood TD, Evan GI, Land H. The c-Myc protein induces cell cycle progression and apoptosis through dimerization with Max. EMBO J. 1993;12:5083–5087. [PMC free article] [PubMed] [Google Scholar]

13. Heikkila R, Schwab G, Wichstrom E, Loke SL, Pluznik DH, Watt R, Nackars LM. A c-myc antisense oligodeoxynucleotide inhibits entry into S-phase but not progress from G0 to G1. Nature. 1987;328:445–449. [PubMed] [Google Scholar]

14. Graeber TG, Osmanian C, Jacks T, Houseman DE, Koch CJ, Lowe SW, Giaccia AJ. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumors. Nature. 1996;379:88–91. [PubMed] [Google Scholar]

15. Wagner AJ, Small MB, Hay N. Myc-mediated apoptosis is blocked by ectopic expression of Bcl-2. Mol Cell Biol. 1993;13:2432–2440. [PMC free article] [PubMed] [Google Scholar]

16. Galaktionov K, Chen X, Beach D. Cdc25 cell cycle phosphatases as a target of c-myc. Nature. 1996;382:511–517. [PubMed] [Google Scholar]

17. Levine A. p53, the cellular gatekeeper for growth and division. Cell. 1997;88:323–331. [PubMed] [Google Scholar]

18. Mosner J, Mummenbrauer T, Bauer C, Sczakiel G, Grosse F, Deppert W. Negative feedback regulation of wild-type p53 synthesis. EMBO J. 1995;14:4442–4449. [PMC free article] [PubMed] [Google Scholar]

19. Agarwal ML, Taylor WR, Chernov MV, Chernova OB, Stark GR. The p53 network. J Biol Chem. 1998;273:1–4. [PubMed] [Google Scholar]

20. Schneider E, Montenarh M, Wagner P. Regulation of CAK kinase activity by p53. Oncogene. 1998;17:2733–2741. [PubMed] [Google Scholar]

21. Agarwal ML, Agarwal A, Taylor WR, Stark GR. p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proc Natl Acad Sci USA. 1995;92:8493–8497. [PMC free article] [PubMed] [Google Scholar]

22. Innocente SA, Abrahamson JLA, Cogswell JP, Lee JM. p53 regulates a G2 checkpoint through cyclin B1. Proc Natl Acad Sci USA. 1999;96:2147–2152. [PMC free article] [PubMed] [Google Scholar]

23. Hermeking H, Lengauer C, Polyak K, He TC, Zhang L, Thiagalingam S, Kinzler KW, Vogelstein B. 14-3-3 Sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell. 1997;1:3–11. [PubMed] [Google Scholar]

24. Di Leonardo A, Khan SH, Linke SP, Greco V, Seidita G, Wahl GM. DNA re-replication in presence of mitotic spindle inhibitors in human and mouse fibroblasts lacking either p53 or pRb function. Cancer Res. 1997;57:1013–1019. [PubMed] [Google Scholar]

25. Brown CR, Doxsey SJ, White, Welch WJ. Both viral (adenovirus E1B) and cellular (hsp70, p53) components interact with centrosomes. J Cell Physiol. 1994;160:47–60. [PubMed] [Google Scholar]

26. Fukasawa K, Choi T, Kuriyama R, Rulong S, Vande Woude GF. Abnormal centrosome amplification in the absence of p53. Science. 1996;271:1744–1747. [PubMed] [Google Scholar]

27. Haupt Y, Rowan S, Shaulian E, Vousden KH, Oren M. Induction of apoptosis in HeLa cells by transactivation-deficient p53. Genes Dev. 1995;9:2170–2183. [PubMed] [Google Scholar]

28. Miyashita T, Harigai M, Hanada M, Reed JC. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 1994;54:3131–3135. [PubMed] [Google Scholar]

29. Wang XW, Vermeulen W, Coursen JD, Gibson M, Lupold SE, Forrester K, Xu G, Elmore L, Yeh H, Hoeijmakers JH, Harris CC. The XPB and XPD DNA helicases are components of the p53-mediated apoptosis. Genes Dev. 1996;10:1219–1232. [PubMed] [Google Scholar]

30. Owen-Schaub LB, Zhang W, Cusack JC, Angelo LS, Santee SM, Fujiwara T, Roth JA, Deisseroth AB, Zhang WW, Kruzel E, Radinsky R. Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol. 1995;15:3032–3040. [PMC free article] [PubMed] [Google Scholar]

31. Wu GS, Burns TF, McDonald ER, III, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G, El-Deiry WS. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet. 1997;17:141–143. [PubMed] [Google Scholar]

32. Polyak K, Waldman T, He TC, Kinzlre KW, Vogestein B. Genetic determinants of p53-induced apoptosis and growth arrest. Genes Dev. 1996;10:1945–1952. [PubMed] [Google Scholar]

33. Debbas M, White E. Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev. 1993;7:546–554. [PubMed] [Google Scholar]

34. Chiou SK, Rao L, White E. Bcl-2 blocks p53-dependent apoptosis. Mol Cell Biol. 1994;14:2556–2563. [PMC free article] [PubMed] [Google Scholar]

35. El-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrel M, Hill DE, Wang Y, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994;54:1169–1174. [PubMed] [Google Scholar]

36. Sherr CJ. Tumor surveillance via the ARF-p53 pathway. Genes Dev. 1998;12:2984–2991. [PubMed] [Google Scholar]

37. Jacks T, Fazeli A, Schmitt E, Branson R, Goodell M, Weinberg R. Effects of an Rb mutation in the mouse. Nature. 1992;359:295–300. [PubMed] [Google Scholar]

38. Fan G, Ma X, Kren BT, Steer CJ. The retinoblastoma gene product inhibits TGF-β1 induced apoptosis in primary rat hepatocytes and in human HuH-7 hepatoma cells. Oncogene. 1996;12:1909–1919. [PubMed] [Google Scholar]

39. Berry DE, Lu Y, Schmidt B, Fallon PG, O'Connell, Hu SX, Xu HJ, Blanck G. Retinoblastoma protein inhibits IFNγ-induced apoptosis. Oncogene. 1996;12:1809–1819. [PubMed] [Google Scholar]

40. Haas-Kogan DA, Kogan SC, Levi D, Dazin P, T'ang A, Fung YK, Israel MA. Inhibition of apoptosis by the retinoblastoma gene product. EMBO J. 1995;14:461–472. [PMC free article] [PubMed] [Google Scholar]

41. An B, Dou QP. Cleavage of retinoblastoma protein during apoptosis: an interleukin 1 beta-converting enzyme-like protease as a candidate. Cancer Res. 1996;56:438–442. [PubMed] [Google Scholar]

42. Dou QP, An B, Antoku K, Johnson DE. Fas stimulation induces RB dephosphorylation and proteolysis that is blocked by inhibitors of the ICE protease family. J Cell Biochem. 1997;64:586–594. [PubMed] [Google Scholar]

43. Janicke RU, Walker PA, Lin XY, Porter AG. Specific cleavage of the retinoblastoma protein by an ICE-like protease in apoptosis. EMBO J. 1996;15:6969–6978. [PMC free article] [PubMed] [Google Scholar]

44. Erhardt P, Tomaselli KJ, Cooper GM. Identification of the MDM2 oncoprotein as a substrate for CPP32-like apoptotic proteases. J Biol Chem. 1997;272:15049–15052. [PubMed] [Google Scholar]

45. Williams BO, Remington L, Albert DM, Mukai S, Branson RT, Jacks T. Cooperative tumorigenic effects of germline mutations in Rb and p53. Nat Genet. 1994;7:480–484. [PubMed] [Google Scholar]

46. Pan H, Griep E. Altered cell cycle regulation in the lens of HPV-16 E6 or E7 transgenic mice: implication for tumor suppressor gene function in development. Genes Dev. 1994;8:1285–1299. [PubMed] [Google Scholar]

47. Fromm L, Shawlot W, Gunning K, Butel JS, Overbeek PA. The retinoblastoma binding region of simian virus 40 large T antigen alters cell cycle regulation in lenses of transgenic mice. Mol Cell Biol. 1994;14:6743–6754. [PMC free article] [PubMed] [Google Scholar]

48. McCarthy SA, Symonds HS, Van Dyke T. Regulation of apoptosis in transgenic mice by simian virus 40 T antigen-mediated inactivation of p53. Proc Natl Acad Sci USA. 1994;92:3979–3983. [PMC free article] [PubMed] [Google Scholar]

49. Lee MH, Williams BO, Mulligan G, Mukai S, Branson RT, Kyson N, Harlow E, Jacks T. Target disruption of p107: functional overlap between p107 and pRb. Genes Dev. 1996;16:1621–1632. [PubMed] [Google Scholar]

50. Harvey KJ, Blomquist JF, Ucker DS. Commitment and effector phases of physiological cell death pathway elucidated with respect to Bcl-2, caspase and cyclin-dependent kinase activities. Mol Cell Biol. 1998;18:2912–2922. [PMC free article] [PubMed] [Google Scholar]

51. Li CJ, Friedman DJ, Wang C, Metelev V, Pardee AB. Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein. Science. 1995;268:429–431. [PubMed] [Google Scholar]

52. Meikrantz W, Gisselbrecht S, Tam S, Schlegel R. Activation of cyclin A-dependent protein kinases during apoptosis. Proc Natl Acad Sci USA. 1994;91:3754–3758. [PMC free article] [PubMed] [Google Scholar]

53. Gil-Gomez G, Berns A, Brady HJM. A link between cell cycle and cell death: Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis. EMBO J. 1998;17:7209–7218. [PMC free article] [PubMed] [Google Scholar]

54. Chen YN, Sharma SK, Ramsey TM, Jiang L, Martin MS, Baker K, Adams PD, Bair KW, Kaelin WG. Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonist. Proc Natl Acad Sci USA. 1999;13:4221–4223. [PMC free article] [PubMed] [Google Scholar]

55. Kasten MM, Giordano A. pRb and the cdks in apoptosis and the cell cycle. Cell Death Differ. 1998;5 1342-140. [PubMed] [Google Scholar]

56. Ling YH, Consoli U, Tornos C, Andreef M, Perez-Soler R. Accumulation of cyclin B, activation of cyclin B1-dependent kinase and induction of programmed cell death in human epidermoid carcinoma KB cells treated with taxol. Int J Cancer. 1998;75:925–932. [PubMed] [Google Scholar]

57. Lahti JM, Xiang J, Heath LS, Campana D, Kidd VJ. PITSLRE protein kinase activity is associated with apoptosis. Mol Cell Biol. 1995;15:1–11. [PMC free article] [PubMed] [Google Scholar]

58. Beyaert R, Kidd VJ, Cornelis S, Van de Craen M, Denecker G, Lahiti JM, Gururajan R, Vandenabeele P, Fiers W. Cleavage of PITSLRE kinases by ICE/CASP1 and CPP32/CASP3 during apoptosis induced by tumor necrosis factor. J Biol Chem. 1997;272:11694–11697. [PubMed] [Google Scholar]

59. Tang D, Gururajan R, Kidd VJ. Phosphorylation of PITSLRE p110 isoforms accompanies their processing by caspases during Fas-meditated cell death. J Biol Chem. 1998;273:16601–16607. [PubMed] [Google Scholar]

60. Han EK, Begemann M, Sgambato A, Soh JW, Doki Y, Xing WQ, Liu W, Weinsten IB. Increased expression of cyclin D1 in a murine mammary epithelial cell line induces p27Kip1, inhibits growth and enhanced apoptosis. Cell Growth Differ. 1996;7:699–710. [PubMed] [Google Scholar]

61. Janicke RU, Lin XY, Porter AG. Cyclin D3 sensitizes tumor cells to TNF-induced, c-Myc-dependent apoptosis. Mol Cell Biol. 1996;16:5245–5253. [PMC free article] [PubMed] [Google Scholar]

62. Wang J, Walsh K. Resistance to apoptosis conferred by CDK inhibitors during myocyte differentiation. Science. 1996;273:359–361. [PMC free article] [PubMed] [Google Scholar]

63. Poluha W, Poluha D, Chang B, Crosbie NE, Schonhoff CM, Kilpatrick DL, Ross AH. The cyclin-dependent kinase inhibitor p21WAF1 is required for survival of differentiating neuroblastoma cells. Mol Cell Biol. 1996;16:1335–1341. [PMC free article] [PubMed] [Google Scholar]

64. Lu Y, Yamagishi N, Yagi T, Takebe H. Mutated p21(WAF1/CIP1/SDI1) lacking CDK-inhibitory activity fails to prevent apoptosis in human colorectal carcinoma cells. Oncogene. 1998;16:705–712. [PubMed] [Google Scholar]

65. Wang X, Gorospe M, Huang Y, Holbrook NJ. p27Kip1 overexpression causes apoptotic death of mammalian cells. Oncogene. 1997;15:2991–2997. [PubMed] [Google Scholar]

66. Scott DW, Donjerkovic D, Maddox B, Ezhevsky S, Grdina T. Role of c-myc and p27 in anti-IgM-induced B-lymphoma apoptosis. Curr Topics Microbiol Immunol. 1997;224:102–112. [PubMed] [Google Scholar]

67. Hiromura K, Pippin JW, Fero ML, Roberts JM, Shankland SJ. Modulation of apoptosis by the cyclin-dependent kinase inhibitor p27(Kip1) J Clin Invest. 1999;103:597–604. [PMC free article] [PubMed] [Google Scholar]

68. Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM, Russel R. Cleavage of p21CIP1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade. Mol Cell. 1998;1:553–563. [PubMed] [Google Scholar]

69. Gervais JLM, Seth P, Zhang H. Cleavage of CDK inhibitor p21Cip/Waf1 by caspases is an early event during DNA damage-induced apoptosis. J Biol Chem. 1998;273:19207–19212. [PubMed] [Google Scholar]

70. Donato N, Perez M. Tumor necrosis factor-induced apoptosis stimulates p53 accumulation and p21WAF1 proteolysis in ME-180 cells. J Biol Chem. 1998;273:5067–5072. [PubMed] [Google Scholar]

71. Loubat A, Rochet N, Turchi L, Rezzonico R, Far DF, Auberger P, Rossi B, Ponzio G. Evidence for a p23-caspase-cleaved form of p27(KIP1) Oncogene. 1999;18:3324–3333. [PubMed] [Google Scholar]

72. Yan Y, Friesen J, Lee MH, Massague J, Barbacid M. Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. Genes Dev. 1997;11:973–983. [PubMed] [Google Scholar]

73. Hama S, Heike Y, Naruse I, Takahashi M, Yoshioka H, Arita K, Kurisu K, Goldman CK, Curie DT, Saijo N. Adenovirus-mediated p16 gene transfer prevents drug-induced cell death through G1 arrest in human glioma cells. Int J Cancer. 1998;77:47–54. [PubMed] [Google Scholar]

74. Sandig V, Brand K, Herwig S, Lukas J, Bartek J, Strauss M. Adenoviral-transferred p16INK4/CDKN2 and p53 genes cooperate to induce apoptotic tumor cell death. Nat Med. 1997;3:313–319. [PubMed] [Google Scholar]

75. Schreiber M, Muller WJ, Singh G, Graham FL. Comparison of the effectiveness of adenovirus vectors expressing cyclin kinase inhibitors p16INK4A, p18INK4C, p19INK4D, p21 (WAF1/CIP1) and p27KIP1 in inducing cell cycle arrest, apoptosis and inhibition of tumorigenicity. Oncogene. 1999;18:1663–1676. [PubMed] [Google Scholar]

76. Pucci B, Giordano A. Cell cycle and cancer. Clin Ter. 1999;150:135–141. [PubMed] [Google Scholar]