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Mouse Models of Cell Cycle Regulators: New Paradigms

  • Eiman Aleem
  • Philipp KaldisEmail author
Chapter
Part of the Results and Problems in Cell Differentiation book series (RESULTS, volume 42)

Abstract

In yeast, a single cyclin-dependent kinase (Cdk) is able to regulate diverse cell cycle transitions (S and M phases) by associating with multiple stage-specific cyclins. The evolution of multicellular organisms brought additional layers of cell cycle regulation in the form of numerous Cdks, cyclins and Cdk inhibitors to reflect the higher levels of organismal complexity. Our current knowledge about the mammalian cell cycle emerged from early experiments using human and rodent cell lines, from which we built the current textbook model of cell cycle regulation. In this model, the functions of different cyclin/Cdk complexes were thought to be specific for each cell cycle phase. In the last decade, studies using genetically engineered mice in which cell cycle regulators were targeted revealed many surprises. We discovered the in vivo functions of cell cycle proteins within the context of a living animal and whether they are essential for animal development. In this review, we discuss first the textbook model of cell cycle regulation, followed by a global overview of data obtained from different mouse models. We describe the similarities and differences between the phenotypes of different mouse models including embryonic lethality, sterility, hematopoietic, pancreatic, and placental defects. We also describe the role of key cell cycle regulators in the development of tumors in mice, and the implications of these data for human cancer. Furthermore, animal models in which two or more genes are ablated revealed which cell cycle regulators interact genetically and functionally complement each other. We discuss for example the interaction of cyclin D1 and p27 and the compensation of Cdk2 by Cdc2. We also focus on new functions discovered for certain cell cycle regulators such as the regulation of S phase by Cdc2 and the role of p27 in regulating cell migration. Finally, we conclude the chapter by discussing the limitations of animal models and to what extent can the recent findings be reconciled with the past work to come up with a new model for cell cycle regulation with high levels of redundancy among the molecular players.

Keywords

Cell Cycle Regulator Phase Entry Trophoblast Giant Cell Mammalian Cell Cycle Wild Type MEFs 
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.

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Notes

Acknowledgments

We thank Cyril Berthet for discussion, support, and communication of unpublished results. We are grateful to all members of the Kaldis lab for their support. We are also indebted to Nancy Jenkins and Neal Copeland and all members of the Mouse Cancer Genetics Program, at the NCI-Frederick for their thoughtful discussions and continuous support. Our thanks extend also to Hiroaki Kiyokawa, Northwestern, and Michele Pagano, NYU, for support and discussions. The work in our laboratory was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

References

  1. 1.
    Ait-Si-Ali S, Ramirez S, Barre FX, Dkhissi F, Magnaghi-Jaulin L, Girault JA, Robin P, Knibiehler M, Pritchard LL, Ducommun B, Trouche D, Harel-Bellan A (1998) Histone acetyltransferase activity of CBP is controlled by cycle-dependent kinases and oncoprotein E1A. Nature 396:184–186 PubMedCrossRefGoogle Scholar
  2. 2.
    Al-Aynati MM, Radulovich N, Ho J, Tsao MS (2004) Overexpression of G1-S cyclins and cyclin-dependent kinases during multistage human pancreatic duct cell carcinogenesis. Clin Cancer Res 10:6598–6605 PubMedCrossRefGoogle Scholar
  3. 3.
    Aleem E, Berthet C, Kaldis P (2004) Cdk2 as a master of S phase entry: fact or fake? Cell Cycle 3:35–37 PubMedCrossRefGoogle Scholar
  4. 4.
    Aleem E, Kiyokawa H, Kaldis P (2005) Cdc2-cyclin E complexes regulate the G1/S phase transition. Nat Cell Biol 7:831–836 PubMedCrossRefGoogle Scholar
  5. 5.
    Amano M, Chihara K, Kimura K, Fukata Y, Nakamura N, Matsuura Y, Kaibuchi K (1997) Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase. Science 275:1308–1311 PubMedCrossRefGoogle Scholar
  6. 6.
    Amon A, Irniger S, Nasmyth K (1994) Closing the cell cycle circle in yeast: G2 cyclin proteolysis initiated at mitosis persists until the activation of G1 cyclins in the next cycle. Cell 77:1037–1050 PubMedCrossRefGoogle Scholar
  7. 7.
    Arata Y, Fujita M, Ohtani K, Kijima S, Kato JY (2000) Cdk2-dependent and -independent pathways in E2F-mediated S phase induction. J Biol Chem 275:6337–6345 PubMedCrossRefGoogle Scholar
  8. 8.
    Ashley T, Walpita D, de Rooij DG (2001) Localization of two mammalian cyclin dependent kinases during mammalian meiosis. J Cell Sci 114:685–693 PubMedGoogle Scholar
  9. 9.
    Bartek J, Lukas C, Lukas J (2004) Checking on DNA damage in S phase. Nat Rev Mol Cell Biol 5:792–804 PubMedCrossRefGoogle Scholar
  10. 10.
    Bartkova J, Lukas J, Muller H, Lutzhoft D, Strauss M, Bartek J (1994) Cyclin D1 protein expression and function in human breast cancer. Int J Cancer 57:353–361 PubMedCrossRefGoogle Scholar
  11. 11.
    Bartkova J, Lukas J, Strauss M, Bartek J (1998) Cyclin D3: requirement for G1/S transition and high abundance in quiescent tissues suggest a dual role in proliferation and differentiation. Oncogene 17:1027–1037 PubMedCrossRefGoogle Scholar
  12. 12.
    Bashir T, Pagano M (2005) Cdk1: the dominant sibling of Cdk2. Nat Cell Biol 7:779–781 PubMedCrossRefGoogle Scholar
  13. 13.
    Bell GI, Polonsky KS (2001) Diabetes mellitus and genetically programmed defects in beta-cell function. Nature 414:788–791 PubMedCrossRefGoogle Scholar
  14. 14.
    Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P (2003) Cdk2 knockout mice are viable. Curr Biol 13:1775–1785 PubMedCrossRefGoogle Scholar
  15. 15.
    Besson A, Gurian-West M, Schmidt A, Hall A, Roberts JM (2004) p27Kip1 modulates cell migration through the regulation of RhoA activation. Genes Dev 18:862–876 PubMedCrossRefGoogle Scholar
  16. 16.
    Beumer TL, Kiyokawa H, Roepers-Gajadien HL, van den Bos LA, Lock TM, Gademan IS, Rutgers DH, Koff A, de Rooij DG (1999) Regulatory role of p27Kip1 in the mouse and human testis. Endocrinology 140:1834–1840 PubMedCrossRefGoogle Scholar
  17. 17.
    Bloom J, Pagano M (2003) Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Semin Cancer Biol 13:41–47 PubMedCrossRefGoogle Scholar
  18. 18.
    Bonner-Weir S, Toschi E, Inada A, Reitz P, Fonseca SY, Aye T, Sharma A (2004) The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatr Diabetes 5 Suppl 2:16–22 Google Scholar
  19. 19.
    Booher RN, Alfa CE, Hyams JS, Beach DH (1989) The fission yeast cdc2/cdc13/suc1 protein kinase: regulation of catalytic activity and nuclear localization. Cell 58:485–497 PubMedCrossRefGoogle Scholar
  20. 20.
    Bortner DM, Rosenberg MP (1997) Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E. Mol Cell Biol 17:453–459 PubMedGoogle Scholar
  21. 21.
    Brandeis M, Rosewell I, Carrington M, Crompton T, Jacobs AM, Kirk J, Gannon J, Hunt T (1998) Cyclin B2-null mice develp normally and are fertile whereas cyclin B1-null mice die in utero. Proc Natl Acad Sci USA 95:4344–4349 PubMedCrossRefGoogle Scholar
  22. 22.
    Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110 PubMedCrossRefGoogle Scholar
  23. 23.
    Carneiro C, Jiao MS, Hu M, Shaffer D, Park M, Pandolfi PP, Cordon-Cardo C, Koff A (2003) p27 deficiency desensitizes Rb –/– cells to signals that trigger apoptosis during pituitary tumor development. Oncogene 22:361–369 PubMedCrossRefGoogle Scholar
  24. 24.
    Carrano AC, Eytan E, Hershko A, Pagano M (1999) SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1:193–199 PubMedCrossRefGoogle Scholar
  25. 25.
    Chapman DL, Wolgemuth DJ (1992) Identification of a mouse B-type cyclin which exhibits developmentally regulated expression in the germ line. Mol Reprod Dev 33:259–269 PubMedCrossRefGoogle Scholar
  26. 26.
    Chapman DL, Wolgemuth DJ (1993) Isolation of the murine cyclin B2 cDNA and characterization of the lineage and temporal specificity of expression of the B1 and B2 cyclins during oogenesis, spermatogenesis and early embryogenesis. Development 118:229–240 PubMedGoogle Scholar
  27. 27.
    Chen Z, Indjeian VB, McManus M, Wang L, Dynlacht BD (2002) CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells. Dev Cell 3:339–350 PubMedCrossRefGoogle Scholar
  28. 28.
    Cheng A, Ross KE, Kaldis P, Solomon MJ (1999) Dephosphorylation of cyclin-dependent kinases by type 2C protein phosphatases. Genes Dev 13:2946–2957 PubMedCrossRefGoogle Scholar
  29. 29.
    Chevalier S, Tassan JP, Cox R, Philippe M, Ford C (1995) Both cdc2 and cdk2 promote S phase initiation in Xenopus egg extracts. J Cell Sci 108:1831–1841 PubMedGoogle Scholar
  30. 30.
    Ciemerych MA, Kenney AM, Sicinska E, Kalaszczynska I, Bronson RT, Rowitch DH, Gardner H, Sicinski P (2002) Development of mice expressing a single D-type cyclin. Genes Dev 16:3277–3289 PubMedCrossRefGoogle Scholar
  31. 31.
    Ciemerych MA, Sicinski P (2005) Cell cycle in mouse development. Oncogene 24:2877–2898 PubMedCrossRefGoogle Scholar
  32. 32.
    Clark AJ, Doyle KM, Humbert PO (2004) Cell-intrinsic requirement for pRb in erythropoiesis. Blood 104:1324–1326 PubMedCrossRefGoogle Scholar
  33. 33.
    Clarke PR, Leiss D, Pagano M, Karsenti E (1992) Cyclin A- and cyclin B-dependent protein kinases are regulated by different mechanisms in Xenopus egg extraacts. EMBO J 11:1751–1761 PubMedGoogle Scholar
  34. 34.
    Cobrinik D, Lee MH, Hannon G, Mulligan G, Bronson RT, Dyson N, Harlow E, Beach D, Weinberg RA, Jacks T (1996) Shared role of the pRB-related p130 and p107 proteins in limb development. Genes Dev 10:1633–1644 PubMedCrossRefGoogle Scholar
  35. 35.
    Collard JG (2004) Cancer: Kip moving. Nature 428:705–708 PubMedCrossRefGoogle Scholar
  36. 36.
    Connell-Crowley L, Elledge SJ, Harper JW (1998) G1 cyclin-dependent kinases are sufficient to initiate DNA synthesis in quiescent human fibroblasts. Curr Biol 8:65–68 PubMedCrossRefGoogle Scholar
  37. 37.
    Correa-Bordes J, Nurse P (1995) p25rum1 orders S phase and mitosis by acting as an inhibitor of the p34cdc2 mitotic kinase. Cell 83:1001–1009 PubMedCrossRefGoogle Scholar
  38. 38.
    Cross FR (1988) DAF1, a mutant gene affecting size control, pheromone arrest, and cell cycle kinetics of Saccharomyces cerevisiae. Mol Cell Biol 8:4675–4684 PubMedGoogle Scholar
  39. 39.
    Di Cristofano A, De Acetis M, Koff A, Cordon-Cardo C, Pandolfi PP (2001) Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nat Genet 27:222–224 PubMedCrossRefGoogle Scholar
  40. 40.
    Dickson C, Fantl V, Gillett C, Brookes S, Bartek J, Smith R, Fisher C, Barnes D, Peters G (1995) Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancer. Cancer Lett 90:43–50 PubMedCrossRefGoogle Scholar
  41. 41.
    Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356:215–221 PubMedCrossRefGoogle Scholar
  42. 42.
    Dor Y, Brown J, Martinez OI, Melton DA (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429:41–46 PubMedCrossRefGoogle Scholar
  43. 43.
    Draetta G, Beach D (1988) Activation of cdc2 protein kinase during mitosis in human cells: cell cycle-dependent phosphorylation and subunit rearrangement. Cell 54:17–26 PubMedCrossRefGoogle Scholar
  44. 44.
    Draviam VM, Orrechia S, Lowe M, Pardi R, Pines J (2001) The localization of human cyclins B1 and B2 determines CDK1 substrate specificity and neither enzyme requires MEK to disassemble the Golgi apparatus. J Cell Biol 152:945–958 PubMedCrossRefGoogle Scholar
  45. 45.
    Dulic V, Lees E, Reed SI (1992) Association of human cyclin E with a periodic G1-S phase protein kinase. Science 257:1958–1961 PubMedCrossRefGoogle Scholar
  46. 46.
    Edgar BA, Lehner CF (1996) Developmental control of cell cycle regulators: a fly's perspective. Science 274:1646–1652 PubMedCrossRefGoogle Scholar
  47. 47.
    Eggan K, Akutsu H, Loring J, Jackson-Grusby L, Klemm M, Rideout WM III, Yanagimachi R, Jaenisch R (2001) Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation. Proc Natl Acad Sci USA 98:6209–6214 PubMedCrossRefGoogle Scholar
  48. 48.
    Elledge SJ, Richman R, Hall FL, Williams RT, Lodgson N, Harper JW (1992) CDK2 encodes a 33-kDa cyclin A-associated protein kinase and is expressed before CDC2 in the cell cycle. Proc Natl Acad Sci USA 89:2907–2911 PubMedCrossRefGoogle Scholar
  49. 49.
    Elledge SJ, Spottswood MR (1991) A new human p34 protein kinase, CDK2, identified by complementation of a cdc28 mutation in Saccharomyces cerevisiae, is a homolog of Xenopus Eg1. EMBO J 10:2653–2659 PubMedGoogle Scholar
  50. 50.
    Fang F, Newport JW (1991) Evidence that the G1-S and G2-M transitions are controlled by different cdc2 proteins in higher eukaryotes. Cell 66:731–742 PubMedCrossRefGoogle Scholar
  51. 51.
    Fantl V, Stamp G, Andrews A, Rosewell I, Dickson C (1995) Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev 9:2364–2372 PubMedCrossRefGoogle Scholar
  52. 52.
    Fehling HJ, Krotkova A, Saint-Ruf C, von Boehmer H (1995) Crucial role of the pre-T-cell receptor alpha gene in development of alpha beta but not gamma delta T cells. Nature 375:795–798 PubMedCrossRefGoogle Scholar
  53. 53.
    Felzien LK, Farrell S, Betts JC, Mosavin R, Nabel GJ (1999) Specificity of cyclin E-Cdk2, TFIIB, and E1A interactions with a common domain of the p300 coactivator. Mol Cell Biol 19:4241–4246 PubMedGoogle Scholar
  54. 54.
    Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ (1998) The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature 396:177–180 PubMedCrossRefGoogle Scholar
  55. 55.
    Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM, Kaushansky K, Roberts JM (1996) A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27Kip1-deficient mice. Cell 85:733–744 PubMedCrossRefGoogle Scholar
  56. 56.
    Firpo EJ, Koff A, Solomon MJ, Roberts JM (1994) Inactivation of a Cdk2 inhibitor during interleukin 2-induced proliferation of human T lymphocytes. Mol Cell Biol 14:4889–4901 PubMedGoogle Scholar
  57. 57.
    Fischer PM, Gianella-Borradori A (2003) CDK inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 12:955–970 PubMedCrossRefGoogle Scholar
  58. 58.
    Fisher D, Nurse P (1995) Cyclins of the fission yeast Schizosaccharomyces pombe. Semin Cell Biol 2:73–78 CrossRefGoogle Scholar
  59. 59.
    Fisher D, Nurse P (1996) A single fission yeast mitotic cyclin B p34cdc2 kinase promotes both S-phase and mitosis in the absence of G1 cyclins. EMBO J 15:850–860 PubMedGoogle Scholar
  60. 60.
    Franklin DS, Godfrey VL, Lee H, Kovalev GI, Schoonhoven R, Chen-Kiang S, Su L, Xiong Y (1998) CDK inhibitors p18INK4c and p27Kip1 mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes Dev 12:2899–2911 PubMedCrossRefGoogle Scholar
  61. 61.
    Fukuse T, Hirata T, Naiki H, Hitomi S, Wada H (2000) Prognostic significance of cyclin E overexpression in resected non-small cell lung cancer. Cancer Res 60:242–244 PubMedGoogle Scholar
  62. 62.
    Furstenthal L, Swanson C, Kaiser BK, Eldridge AG, Jackson PK (2001) Triggering ubiquitination of a CDK inhibitor at origins of DNA replication. Nat Cell Biol 3:715–722 PubMedCrossRefGoogle Scholar
  63. 63.
    Furuno N, den Elzen N, Pines J (1999) Human cyclin A is required for mitosis until mid prophase. J Cell Biol 147:295–306 PubMedCrossRefGoogle Scholar
  64. 64.
    Gallant P, Nigg EA (1994) Identification of a novel vertebrate cyclin: cyclin B3 shares properties with both A- and B-type cyclins. EMBO J 13:595–605 PubMedGoogle Scholar
  65. 65.
    Geisen C, Moroy T (2002) The oncogenic activity of cyclin E is not confined to Cdk2 activation alone but relies on several other, distinct functions of the protein. J Biol Chem 277:39909–39918 PubMedCrossRefGoogle Scholar
  66. 66.
    Geng Y, Whoriskey W, Park MY, Bronson RT, Medema RH, Li T, Weinberg RA, Sicinski P (1999) Rescue of cyclin D1 deficiency by knockin cyclin E. Cell 97:767–777 PubMedCrossRefGoogle Scholar
  67. 67.
    Geng Y, Yu Q, Sicinska E, Das M, Bronson RT, Sicinski P (2001a) Deletion of the p27Kip1 gene restores normal development in cyclin D1-deficient mice. Proc Natl Acad Sci USA 98:194–199 PubMedCrossRefGoogle Scholar
  68. 68.
    Geng Y, Yu Q, Whoriskey W, Dick F, Tsai KY, Ford HL, Biswas DK, Pardee AB, Amati B, Jacks T, Richardson A, Dyson N, Sicinski P (2001b) Expression of cyclins E1 and E2 during mouse development and in neoplasia. Proc Natl Acad Sci USA 98:13138–13143 PubMedCrossRefGoogle Scholar
  69. 69.
    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 114:431–443 PubMedCrossRefGoogle Scholar
  70. 70.
    Georgia S, Bhushan A (2004) Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. J Clin Invest 114:963–968 PubMedGoogle Scholar
  71. 71.
    Gillett C, Fantl V, Smith R, Fisher C, Bartek J, Dickson C, Barnes D, Peters G (1994) Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res 54:1812–1817 PubMedGoogle Scholar
  72. 72.
    Gillett C, Smith P, Gregory W, Richards M, Millis R, Peters G, Barnes D (1996) Cyclin D1 and prognosis in human breast cancer. Int J Cancer 69:92–99 PubMedCrossRefGoogle Scholar
  73. 73.
    Gladden AB, Diehl JA (2003) The cyclin D1-dependent kinase associates with the pre-replication complex and modulates RB-MCM7 binding. J Biol Chem 278:9754–9760 PubMedCrossRefGoogle Scholar
  74. 74.
    Gopalkrishnan RV, Dolle P, Mattei MG, La Thangue NB, Kedinger C (1996) Genomic structure and developmental expression of the mouse cell cycle regulatory transcription factor DP1. Oncogene 13:2671–2680 PubMedGoogle Scholar
  75. 75.
    Grandori C, Eisenman RN (1997) Myc target genes. Trends Biochem Sci 22:177–181 PubMedCrossRefGoogle Scholar
  76. 76.
    Haase SB, Reed SI (1999) Evidence that a free-running oscillator drives G1 events in the budding yeast cell cycle. Nature 401:394–397 PubMedGoogle Scholar
  77. 77.
    Hadwiger JA, Wittenberg C, Richardson HE, de Barros Lopes M, Reed SI (1989) A family of cyclin homologs that control the G1 phase in yeast. Proc Natl Acad Sci USA 86:6255–6259 PubMedCrossRefGoogle Scholar
  78. 78.
    Hagting A, Karlsson C, Clute P, Jackman M, Pines J (1998) MPF localization is controlled by nuclear export. EMBO J 17:4127–4138 PubMedCrossRefGoogle Scholar
  79. 79.
    Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC (1999) Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 98:859–869 PubMedCrossRefGoogle Scholar
  80. 80.
    Harrison DJ, Hooper ML, Armstrong JF, Clarke AR (1995) Effects of heterozygosity for the Rb-1t19neo allele in the mouse. Oncogene 10:1615–1620 PubMedGoogle Scholar
  81. 81.
    Hartwell LH, Culotti J, Pringle JR, Reid BJ (1974) Genetic control of the cell division cycle in yeast. Science 183:46–51 PubMedCrossRefGoogle Scholar
  82. 82.
    Hayles J, Fisher D, Woollard A, Nurse P (1994) Temopral order of S phase ans mitosis in fission yeast is determined by the state of the p34cdc2-mitotic B cyclin complex. Cell 78:813–822 PubMedCrossRefGoogle Scholar
  83. 83.
    Hedger M, de Kretser D (2000) Leydig cell function and its regulation. Results Probl Cell Differ 28:69–110 PubMedGoogle Scholar
  84. 84.
    Helin K, Wu CL, Fattaey AR, Lees JA, Dynlacht BD, Ngwu C, Harlow E (1993) Heterodimerization of the transcription factors E2F-1 and DP-1 leads to cooperative trans-activation. Genes Dev 7:1850–1861 PubMedCrossRefGoogle Scholar
  85. 85.
    Herskowitz I (1987) Functional inactivation of genes by dominant negative mutations. Nature 329:219–222 PubMedCrossRefGoogle Scholar
  86. 86.
    Hinds PW (2003) Cdk2 dethroned as master of S phase entry. Cancer Cell 3:305–307 PubMedCrossRefGoogle Scholar
  87. 87.
    Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI, Weinberg RA (1992) Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell 70:993–1006 PubMedCrossRefGoogle Scholar
  88. 88.
    Hoffmann I, Draetta G, Karsenti E (1994) Activation of the phosphatase activity of human cdc25A by a cdk2-cyclin E dependent phosphorylation at the G1/S transition. EMBO J 13:4302–4310 PubMedGoogle Scholar
  89. 89.
    Howe JA, Howell M, Hunt T, Newport JW (1995) Identification of a developmental timer regulating the stability of embryonic cyclin A and a new somatic A-type cyclin at gastrulation. Genes Dev 9:1164–1176 PubMedCrossRefGoogle Scholar
  90. 90.
    Hu N, Gutsmann A, Herbert DC, Bradley A, Lee WH, Lee EY (1994) Heterozygous Rb-1 delta 20/+ mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 9:1021–1027 PubMedGoogle Scholar
  91. 91.
    Hwang HC, Clurman BE (2005) Cyclin E in normal and neoplastic cell cycles. Oncogene 24:2776–2786 PubMedCrossRefGoogle Scholar
  92. 92.
    Inaba T, Matsushime H, Valentine M, Roussel MF, Sherr CJ, Look AT (1992) Genomic organization, chromosomal localization, and independent expression of human cyclin D genes. Genomics 13:565–574 PubMedCrossRefGoogle Scholar
  93. 93.
    Ishida N, Hara T, Kamura T, Yoshida M, Nakayama K, Nakayama KI (2002) Phosphorylation of p27Kip1 on serine 10 is required for its binding to CRM1 and nuclear export. J Biol Chem 277:14355–14358 PubMedCrossRefGoogle Scholar
  94. 94.
    Jackman M, Firth M, Pines J (1995) Human cyclins B1 and B2 are localized to strikingly different structures: B1 to microtubules, B2 primarily to the Golgi apparatus. EMBO J 14:1646–1654 PubMedGoogle Scholar
  95. 95.
    Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA (1992) Effects of an Rb mutation in the mouse. Nature 359:295–300 PubMedCrossRefGoogle Scholar
  96. 96.
    Ji P, Jiang H, Rekhtman K, Bloom J, Ichetovkin M, Pagano M, Zhu L (2004) An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant. Mol Cell 16:47–58 PubMedCrossRefGoogle Scholar
  97. 97.
    Jirawatnotai S, Aziyu A, Osmundson EC, Moons DS, Zou X, Kineman RD, Kiyokawa H (2004) Cdk4 is indispensable for postnatal proliferation of the anterior pituitary. J Biol Chem 279:51100–51106 PubMedCrossRefGoogle Scholar
  98. 98.
    Kaldis P, Aleem E (2005) Cell cycle sibling rivalry: Cdc2 vs. Cdk2. Cell Cycle 4:1491–1494 PubMedCrossRefGoogle Scholar
  99. 99.
    Keyomarsi K, Tucker SL, Buchholz TA, Callister M, Ding Y, Hortobagyi GN, Bedrosian I, Knickerbocker C, Toyofuku W, Lowe M, Herliczek TW, Bacus SS (2002) Cyclin E and survival in patients with breast cancer. N Engl J Med 347:1566–1575 PubMedCrossRefGoogle Scholar
  100. 100.
    Kim JH, Kang MJ, Park CU, Kwak HJ, Hwang Y, Koh GY (1999) Amplified CDK2 and cdc2 activities in primary colorectal carcinoma. Cancer 85:546–553 PubMedCrossRefGoogle Scholar
  101. 101.
    King RW, Peters J-M, Tugendreich S, Rolfe M, Hieter P, Kirschner MW (1995) A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B. Cell 81:279–288 PubMedCrossRefGoogle Scholar
  102. 102.
    Kitagawa M, Okabe T, Ogino H, Matsumoto H, Suzuki-Takahashi I, Kokubo T, Higashi H, Saitoh S, Taya Y, Yasuda H, et al. (1993) Butyrolactone I, a selective inhibitor of cdk2 and cdc2 kinase. Oncogene 8:2425–2432 PubMedGoogle Scholar
  103. 103.
    Kiyokawa H, Kineman RD, Manova-Todorova KO, Soares VC, Hoffman ES, Ono M, Khanam D, Hayday AC, Frohman LA, Koff A (1996) Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27Kip1. Cell 85:721–732 PubMedCrossRefGoogle Scholar
  104. 104.
    Knoblich JA, Lehner CF (1993) Synergistic action of Drosophila cyclins A and B during the G2-M transition. EMBO J 12:65–74 PubMedGoogle Scholar
  105. 105.
    Koff A, Cross F, Fisher A, Schumacher J, Leguellec K, Philippe M, Roberts JM (1991) Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family. Cell 66:1217–1228 PubMedCrossRefGoogle Scholar
  106. 106.
    Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR, Roberts JM (1992) Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science 257:1689–1694 PubMedCrossRefGoogle Scholar
  107. 107.
    Koff A, Ohtsuki M, Polyak K, Roberts JM, Massague J (1993) Negative regulation of G1 in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-beta. Science 260:536–539 PubMedCrossRefGoogle Scholar
  108. 108.
    Kohn MJ, Bronson RT, Harlow E, Dyson NJ, Yamasaki L (2003) Dp1 is required for extra-embryonic development. Development 130:1295–1305 PubMedCrossRefGoogle Scholar
  109. 109.
    Kohn MJ, Leung SW, Criniti V, Agromayor M, Yamasaki L (2004) Dp1 is largely dispensable for embryonic development. Mol Cell Biol 24:7197–7205 PubMedCrossRefGoogle Scholar
  110. 110.
    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 118:477–491 PubMedCrossRefGoogle Scholar
  111. 111.
    Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A (2001) Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 413:83–86 PubMedCrossRefGoogle Scholar
  112. 112.
    Krude T, Jackman M, Pines J, Laskey RA (1997) Cyclin/Cdk-dependent initiation of DNA replication in a human cell-free system. Cell 88:109–119 PubMedCrossRefGoogle Scholar
  113. 113.
    Kushner JA, Ciemerych MA, Sicinska E, Wartschow LM, Teta M, Long SY, Sicinski P, White MF (2005) Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. Mol Cell Biol 25:3752–3762 PubMedCrossRefGoogle Scholar
  114. 114.
    Lahue EE, Smith AV, Orr-Weaver TL (1991) A novel cyclin gene from Drosophila complements CLN function in yeast. Genes Dev 5:2166–2175 PubMedCrossRefGoogle Scholar
  115. 115.
    Latres E, Malumbres M, Sotillo R, Martin J, Ortega S, Martin-Caballero J, Flores JM, Cordon-Cardo C, Barbacid M (2000) Limited overlapping roles of p15INK4b and p18INK4c cell cycle inhibitors in proliferation and tumorigenesis. EMBO J 19:3496–3506 PubMedCrossRefGoogle Scholar
  116. 116.
    Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Herrup K, Lee WH, Bradley A (1992) Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359:288–294 PubMedCrossRefGoogle Scholar
  117. 117.
    Lee MG, Nurse P (1987) Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2. Nature 327:31–35 PubMedCrossRefGoogle Scholar
  118. 118.
    Lees E, Faha B, Dulic V, Reed SI, Harlow E (1992) Cyclin E/cdk2 and cyclin A/cdk2 kinases associate with p107 and E2F in a temporally distinct manner. Genes Dev 6:1874–1885 PubMedCrossRefGoogle Scholar
  119. 119.
    Lehner CF, O'Farrell PH (1989) Expression and function of Drosophila cyclin A during embryonic cell cycle progression. Cell 56:957–968 PubMedCrossRefGoogle Scholar
  120. 120.
    Leung T, Chen XQ, Manser E, Lim L (1996) The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton. Mol Cell Biol 16:5313–5327 PubMedGoogle Scholar
  121. 121.
    Li JQ, Miki H, Ohmori M, Wu F, Funamoto Y (2001) Expression of cyclin E and cyclin-dependent kinase 2 correlates with metastasis and prognosis in colorectal carcinoma. Hum Pathol 32:945–953 PubMedCrossRefGoogle Scholar
  122. 122.
    Liu D, Matzuk MM, Sung WK, Guo Q, Wang P, Wolgemuth DJ (1998) Cyclin A1 is required for meiosis in the male mouse. Nat Genet 20:377–380 PubMedCrossRefGoogle Scholar
  123. 123.
    Loden M, Stighall M, Nielsen NH, Roos G, Emdin SO, Ostlund H, Landberg G (2002) The cyclin D1 high and cyclin E high subgroups of breast cancer: separate pathways in tumorogenesis based on pattern of genetic aberrations and inactivation of the pRb node. Oncogene 21:4680–4690 PubMedCrossRefGoogle Scholar
  124. 124.
    Loeb KR, Kostner H, Firpo E, Norwood T, K DT, Clurman BE, Roberts JM (2005) A mouse model for cyclin E-dependent genetic instability and tumorigenesis. Cancer Cell 8:35–47 PubMedCrossRefGoogle Scholar
  125. 125.
    Lorincz AT, Reed SI (1984) Primary structure homology between the product of yeast cell division control gene CDC28 and vertebrate oncogenes. Nature 307:183–185 PubMedCrossRefGoogle Scholar
  126. 126.
    Lozano JC, Perret E, Schatt P, Arnould C, Peaucellier G, Picard A (2002) Molecular cloning, gene localization, and structure of human cyclin B3. Biochem Biophys Res Commun 291:406–413 PubMedCrossRefGoogle Scholar
  127. 127.
    Lundberg AS, Weinberg RA (1998) Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol Cell Biol 18:753–761 PubMedGoogle Scholar
  128. 128.
    Ma T, Zou N, Lin BY, Chow LT, Harper JW (1999) Interaction between cyclin-dependent kinases and human papillomavirus replication-initiation protein E1 is required for efficient viral replication. Proc Natl Acad Sci USA 96:382–387 PubMedCrossRefGoogle Scholar
  129. 129.
    Maandag EC, van der Valk M, Vlaar M, Feltkamp C, O'Brien J, van Roon M, van der Lugt N, Berns A, te Riele H (1994) Developmental rescue of an embryonic-lethal mutation in the retinoblastoma gene in chimeric mice. EMBO J 13:4260–4268 PubMedGoogle Scholar
  130. 130.
    Madine MA, Swietlik M, Pelizon C, Romanowski P, Mills AD, Laskey RA (2000) The roles of the MCM, ORC, and Cdc6 proteins in determining the replication competence of chromatin in quiescent cells. J Struct Biol 129:198–210 PubMedCrossRefGoogle Scholar
  131. 131.
    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 118:493–504 PubMedCrossRefGoogle Scholar
  132. 132.
    Marraccino RL, Firpo EJ, Roberts JM (1992) Activation of the p34CDC25 protein kinase at the start of S phase in the human cell cycle. Mol Biol Cell 3:389–401 PubMedGoogle Scholar
  133. 133.
    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 p27Kip1 and p21Cip1. Cancer Cell 7:591–598 PubMedCrossRefGoogle Scholar
  134. 134.
    Martin J, Hunt SL, Dubus P, Sotillo R, Nehme-Pelluard F, Magnuson MA, Parlow AF, Malumbres M, Ortega S, Barbacid M (2003) Genetic rescue of Cdk4 null mice restores pancreatic beta-cell proliferation but not homeostatic cell number. Oncogene 22:5261–5269 PubMedCrossRefGoogle Scholar
  135. 135.
    Marzo N, Mora C, Fabregat ME, Martin J, Usac EF, Franco C, Barbacid M, Gomis R (2004) Pancreatic islets from cyclin-dependent kinase 4/R24C (Cdk4) knockin mice have significantly increased beta cell mass and are physiologically functional, indicating that Cdk4 is a potential target for pancreatic beta cell mass regeneration in Type 1 diabetes. Diabetologia 47:686–694 PubMedCrossRefGoogle Scholar
  136. 136.
    Matsumoto Y, Maller JL (2004) A centrosomal localization signal in cyclin E required for Cdk2-independent S phase entry. Science 306:885–888 PubMedCrossRefGoogle Scholar
  137. 137.
    Matsushime H, Ewen ME, Storm DK, Kato J-y, Hanks SK, Roussel MF, Sherr CJ (1992) Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 71:323–334 PubMedCrossRefGoogle Scholar
  138. 138.
    Matsushime H, Roussel MF, Ashmun RA, Sherr CJ (1991) Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 65:701–713 PubMedCrossRefGoogle Scholar
  139. 139.
    Matushansky I, Radparvar F, Skoultchi AI (2000) Reprogramming leukemic cells to terminal differentiation by inhibiting specific cyclin-dependent kinases in G1. Proc Natl Acad Sci USA 97:14317–14322 PubMedCrossRefGoogle Scholar
  140. 140.
    McAllister SS, Becker-Hapak M, Pintucci G, Pagano M, Dowdy SF (2003) Novel p27Kip1 C-terminal scatter domain mediates Rac-dependent cell migration independent of cell cycle arrest functions. Mol Cell Biol 23:216–228 PubMedCrossRefGoogle Scholar
  141. 141.
    McIntosh GG, Anderson JJ, Milton I, Steward M, Parr AH, Thomas MD, Henry JA, Angus B, Lennard TW, Horne CH (1995) Determination of the prognostic value of cyclin D1 overexpression in breast cancer. Oncogene 11:885–891 PubMedGoogle Scholar
  142. 142.
    Mettus RV, Rane SG (2003) Characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice. Oncogene 22:8413–8421 PubMedCrossRefGoogle Scholar
  143. 143.
    Meyerson M, Enders GH, Wu C-L, Su L-K, Gorka C, Nelson C, Harlow E, Tsai L-H (1992) A family of human cdc2-related protein kinases. EMBO J 11:2909–2917 PubMedGoogle Scholar
  144. 144.
    Meyerson M, Harlow E (1994) Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol 14:2077–2086 PubMedGoogle Scholar
  145. 145.
    Miliani de Marval PL, Macias E, Rounbehler R, Sicinski P, Kiyokawa H, Johnson DG, Conti CJ, Rodriguez-Puebla ML (2004) Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissues. Mol Cell Biol 24:7538–7547 PubMedCrossRefGoogle Scholar
  146. 146.
    Miller ME, Cross FR (2001) Cyclin specificity: how many wheels do you need on a unicycle? J Cell Sci 114:1811–1820 PubMedGoogle Scholar
  147. 147.
    Minshull J, Golsteyn R, Hill CS, Hunt T (1990) The A- and B-type cyclin associated cdc2 kinases in Xenopus turn on and off at different times in the cell cycle. EMBO J 9:2865–2875 PubMedGoogle Scholar
  148. 148.
    Mitchison JM, Creanor J (1971) Induction synchrony in the fission yeast. Schizosaccharomyces pombe. Exp Cell Res 67:368–374 PubMedCrossRefGoogle Scholar
  149. 149.
    Mondesert O, McGowan C, Russel P (1996) Cig2, a B-type cyclin, promotes the onset of S in Schizosaccharomyces pombe. Mol Cell Biol 16:1527–1533 PubMedGoogle Scholar
  150. 150.
    Moons DS, Jirawatnotai S, Parlow AF, Gibori G, Kineman RD, Kiyokawa H (2002) Pituitary hypoplasia and lactotroph dysfunction in mice deficient for cyclin-dependent kinase-4. Endocrinology 143:3001–3008 PubMedCrossRefGoogle Scholar
  151. 151.
    Moore JD, Kirk JA, Hunt T (2003) Unmasking the S-phase-promoting potential of cyclin B1. Science 300:987–990 PubMedCrossRefGoogle Scholar
  152. 152.
    Moore JD, Kornbluth S, Hunt T (2002) Identification of the nuclear localization signal in Xenopus cyclin E and analysis of its role in replication and mitosis. Mol Biol Cell 13:4388–4400 PubMedCrossRefGoogle Scholar
  153. 153.
    Moreno S, Hayles J, Nurse P (1989) Regulation of p34cdc2 protein kinase during mitosis. Cell 58:361–372 PubMedCrossRefGoogle Scholar
  154. 154.
    Moreno S, Nurse P (1994) Regulation of progression through the G1 phase of the cell cycle by the rum1+ gene. Nature 367:236–242 PubMedCrossRefGoogle Scholar
  155. 155.
    Morgan DO (1997) Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 13:261–291 PubMedCrossRefGoogle Scholar
  156. 156.
    Morgenbesser SD, Williams BO, Jacks T, DePinho RA (1994) p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature 371:72–74 PubMedCrossRefGoogle Scholar
  157. 157.
    Morris L, Allen KE, La Thangue NB (2000) Regulation of E2F transcription by cyclin E-Cdk2 kinase mediated through p300/CBP co-activators. Nat Cell Biol 2:232–239 PubMedCrossRefGoogle Scholar
  158. 158.
    Mueller PR, Coleman TR, Dunphy WG (1995) Cell cycle regulation of a Xenopus Wee1-like kinase. Mol Biol Cell 6:119–134 PubMedGoogle Scholar
  159. 159.
    Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P (1988) Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54:105–115 PubMedCrossRefGoogle Scholar
  160. 160.
    Murphy M, Stinnakre M-G, Senamaud-Beaufort C, Winston NJ, Sweeney C, Kubelka M, Carrington M, Brechot C, Sobczak-Thepot J (1997) Delayed early embryonic lethality following disruption of the murine cyclin A2 gene. Nat Genet 15:83–86 PubMedCrossRefGoogle Scholar
  161. 161.
    Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY, Nakayama K (1996) Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85:707–720 PubMedCrossRefGoogle Scholar
  162. 162.
    Nakayama K, Nagahama H, Minamishima YA, Matsumoto M, Nakamichi I, Kitagawa K, Shirane M, Tsunematsu R, Tsukiyama T, Ishida N, Kitagawa M, Nakayama K, Hatakeyama S (2000) Targeted disruption of Skp2 results in accumulation of cyclin E and p27Kip1, polyploidy and centrosome overduplication. EMBO J 19:2069–2081 PubMedCrossRefGoogle Scholar
  163. 163.
    Nakayama K, Nagahama H, Minamishima YA, Miyake S, Ishida N, Hatakeyama S, Kitagawa M, Iemura S, Natsume T, Nakayama KI (2004) Skp2-mediated degradation of p27 regulates progression into mitosis. Dev Cell 6:661–672 PubMedCrossRefGoogle Scholar
  164. 164.
    Nakayama KI, Hatakeyama S, Nakayama K (2001) Regulation of the cell cycle at the G1-S transition by proteolysis of cyclin E and p27Kip1. Biochem Biophys Res Commun 282:853–860 PubMedCrossRefGoogle Scholar
  165. 165.
    Nash R, Tokiwa G, Anand S, Erickson K, Futcher AB (1988) The WHI1+ gene of Saccharomyces cerevisiae tethers cell division to cell size and is a cyclin homolog. EMBO J 7:4335–4346 PubMedGoogle Scholar
  166. 166.
    Nasmyth K (1996) Viewpoint: putting the cell cycle in order. Science 274:1643–1645 PubMedCrossRefGoogle Scholar
  167. 167.
    Nguyen TB, Manova K, Capodieci P, Lindon C, Bottega S, Wang XY, Refik-Rogers J, Pines J, Wolgemuth DJ, Koff A (2002) Characterization and expression of mammalian cyclin B3, a prepachytene meiotic cyclin. J Biol Chem 277:41960–41969 PubMedCrossRefGoogle Scholar
  168. 168.
    Nieduszynski CA, Murray J, Carrington M (2002) Whole-genome analysis of animal A- and B-type cyclins. Genome Biol 3: RESEARCH0070 Google Scholar
  169. 169.
    Nigg EA (1995) Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle. Bioessays 17:471–480 PubMedCrossRefGoogle Scholar
  170. 170.
    Nikitin A, Lee WH (1996) Early loss of the retinoblastoma gene is associated with impaired growth inhibitory innervation during melanotroph carcinogenesis in Rb+/– mice. Genes Dev 10:1870–1879 PubMedCrossRefGoogle Scholar
  171. 171.
    Nurse P, Bissett Y (1981) Gene required in G1 for commitment to cell cycle and in G2 for control of mitosis in fission yeast. Nature 292:558–560 PubMedCrossRefGoogle Scholar
  172. 172.
    Ohtsubo M, Roberts JM (1993) Cyclin-dependent regulation of G1 in mammalian fibroblasts. Science 259:1908–1912 PubMedCrossRefGoogle Scholar
  173. 173.
    Okuda M, Horn HF, Tarapore P, Tokuyama Y, Smulian AG, Chan PK, Knudsen ES, Hofmann IA, Snyder JD, Bove KE, Fukasawa K (2000) Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 103:127–140 PubMedCrossRefGoogle Scholar
  174. 174.
    Ookata K, Hisanaga S, Okumura E, Kishimoto T (1993) Association of p34cdc2/cyclin B complex with microtubules in starfish oocytes. J Cell Sci 105:873–881 PubMedGoogle Scholar
  175. 175.
    Ortega S, Malumbres M, Barbacid M (2002) Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta 1602:73–87 PubMedGoogle Scholar
  176. 176.
    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 35:25–31 PubMedCrossRefGoogle Scholar
  177. 177.
    Pagano M (2004) Control of DNA synthesis and mitosis by the Skp2-p27-Cdk1/2 axis. Mol Cell 14:414–416 PubMedCrossRefGoogle Scholar
  178. 178.
    Pagano M, Pepperkok R, Verde F, Ansorge W, Draetta G (1992) Cyclin A is required at two points in the human cell cycle. EMBO J 11:961–971 PubMedGoogle Scholar
  179. 179.
    Pardee AB (1974) A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci USA 71:1286–1290 PubMedCrossRefGoogle Scholar
  180. 180.
    Parisi T, Beck AR, Rougier N, McNeil T, Lucian L, Werb Z, Amati B (2003) Cyclins E1 and E2 are required for endoreplication in placental trophoblast giant cells. EMBO J 22:4794–4803 PubMedCrossRefGoogle Scholar
  181. 181.
    Park MS, Rosai J, Nguyen HT, Capodieci P, Cordon-Cardo C, Koff A (1999) p27 and Rb are on overlapping pathways suppressing tumorigenesis in mice. Proc Natl Acad Sci USA 96:6382–6387 PubMedCrossRefGoogle Scholar
  182. 182.
    Perkins ND, Felzien LK, Betts JC, Leung K, Beach DH, Nabel GJ (1997) Regulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator. Science 275:523–527 PubMedCrossRefGoogle Scholar
  183. 183.
    Peters H (1969) The development of the mouse ovary from birth to maturity. Acta Endocrinol (Copenh) 62:98–116 Google Scholar
  184. 184.
    Philipp-Staheli J, Kim KH, Payne SR, Gurley KE, Liggitt D, Longton G, Kemp CJ (2002) Pathway-specific tumor suppression. Reduction of p27 accelerates gastrointestinal tumorigenesis in Apc mutant mice, but not in Smad3 mutant mice. Cancer Cell 1:355–368 PubMedCrossRefGoogle Scholar
  185. 185.
    Philipp-Staheli J, Payne SR, Kemp CJ (2001) p27Kip1: regulation and function of a haploinsufficient tumor suppressor and its misregulation in cancer. Exp Cell Res 264:148–168 PubMedCrossRefGoogle Scholar
  186. 186.
    Pines J, Hunter T (1989) Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2. Cell 58:833–846 PubMedCrossRefGoogle Scholar
  187. 187.
    Pines J, Hunter T (1990) Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B. Nature 346:760–763 PubMedCrossRefGoogle Scholar
  188. 188.
    Pines J, Hunter T (1991) Human cyclins A and B1 are differentially located in the cell and undergo cell cycle-depenent nuclear transport. J Cell Biol 115:1–17 PubMedCrossRefGoogle Scholar
  189. 189.
    Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A (1994) p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev 8:9–22 PubMedCrossRefGoogle Scholar
  190. 190.
    Rane SG, Cosenza SC, Mettus RV, Reddy EP (2002) Germ line transmission of the Cdk4R24C mutation facilitates tumorigenesis and escape from cellular senescence. Mol Cell Biol 22:644–656 PubMedCrossRefGoogle Scholar
  191. 191.
    Rane SG, Dubus P, Mettus RV, Galbreath EJ, Boden G, Reddy EP, Barbacid M (1999) Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia. Nat Genet 22:44–52 PubMedCrossRefGoogle Scholar
  192. 192.
    Ravnik SE, Wolgemuth DJ (1996) The developmentally restricted pattern of expression in the male germ line of a murine cyclin A, cyclin A2, suggests roles in both mitotic and meiotic cell cycles. Dev Biol 173:69–78 PubMedCrossRefGoogle Scholar
  193. 193.
    Ravnik SE, Wolgemuth DJ (1999) Regulation of meiosis during mammalian spermatogenesis: the A-type cyclins and their associated cyclin-dependent kinases are differentially expressed in the germ-cell lineage. Dev Biol 207:408–418 PubMedCrossRefGoogle Scholar
  194. 194.
    Reed SI (1980) The selection of S. cerevisiae mutants defective in the start event of cell division. Genetics 95:561–577 PubMedGoogle Scholar
  195. 195.
    Ren XD, Kiosses WB, Sieg DJ, Otey CA, Schlaepfer DD, Schwartz MA (2000) Focal adhesion kinase suppresses Rho activity to promote focal adhesion turnover. J Cell Sci 113:3673–3678 PubMedGoogle Scholar
  196. 196.
    Resnitzky D, Hengst L, Reed SI (1995) Cyclin A-associated kinase activity is rate limiting for entrance into S phase and is negatively regulated in G1 by p27Kip1. Mol Cell Biol 15:4347–4352 PubMedGoogle Scholar
  197. 197.
    Rhee K, Wolgemuth DJ (1995) Cdk family genes are expressed not only in dividing but also in terminally differentiated mouse germ cells, suggesting their possible function during both cell division and differentiation. Dev Dyn 204:406–420 PubMedGoogle Scholar
  198. 198.
    Riabowol K, Draetta G, Brizuela L, Vandre D, Beach D (1989) The cdc2 kinase is a nuclear protein that is essential for mitosis in mammalian cells. Cell 57:393–401 PubMedCrossRefGoogle Scholar
  199. 199.
    Ridley AJ, Hall A (1992) The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70:389–399 PubMedCrossRefGoogle Scholar
  200. 200.
    Rodier G, Montagnoli A, Di Marcotullio L, Coulombe P, Draetta GF, Pagano M, Meloche S (2001) p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. EMBO J 20:6672–6682 PubMedCrossRefGoogle Scholar
  201. 201.
    Rodriguez-Puebla ML, Miliani de Marval PL, LaCava M, Moons DS, Kiyokawa H, Conti CJ (2002) Cdk4 deficiency inhibits skin tumor development but does not affect normal keratinocyte proliferation. Am J Pathol 161:405–411 PubMedCrossRefGoogle Scholar
  202. 202.
    Rosenblatt J, Gu Y, Morgan DO (1992) Human cyclin-dependent kinase 2 is activated during the S and G2 phases of the cell cycle and associates with cyclin A. Proc Natl Acad Sci USA 89:2824–2828 PubMedCrossRefGoogle Scholar
  203. 203.
    Rounbehler RJ, Rogers PM, Conti CJ, Johnson DG (2002) Inactivation of E2f1 enhances tumorigenesis in a Myc transgenic model. Cancer Res 62:3276–3281 PubMedGoogle Scholar
  204. 204.
    Rounbehler RJ, Schneider-Broussard R, Conti CJ, Johnson DG (2001) Myc lacks E2F1's ability to suppress skin carcinogenesis. Oncogene 20:5341–5349 PubMedCrossRefGoogle Scholar
  205. 205.
    Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T (2003) Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424:223–228 PubMedCrossRefGoogle Scholar
  206. 206.
    Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA (1996) Role of the INK4a locus in tumor suppression and cell mortality. Cell 85:27–37 PubMedCrossRefGoogle Scholar
  207. 207.
    Sharpe RM (1989) Possible role of elongated spermatids in control of stage-dependent changes in the diameter of the lumen of the rat seminiferous tubule. J Androl 10:304–310 PubMedGoogle Scholar
  208. 208.
    Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, DePinho RA (2001) Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413:86–91 PubMedCrossRefGoogle Scholar
  209. 209.
    Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE (1997) Cyclin E-CDK2 is a regulator of p27Kip1. Genes Dev 11:1464–1478 PubMedCrossRefGoogle Scholar
  210. 210.
    Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512 PubMedCrossRefGoogle Scholar
  211. 211.
    Sherr CJ, Roberts JM (2004) Living with or without cyclins and cyclin-dependent kinases. Genes Dev 18:2699–2711 PubMedCrossRefGoogle Scholar
  212. 212.
    Sicinska E, Aifantis I, Le Cam L, Swat W, Borowski C, Yu Q, Ferrando AA, Levin SD, Geng Y, von Boehmer H, Sicinski P (2003) Requirement for cyclin D3 in lymphocyte development and T cell leukemias. Cancer Cell 4:451–461 PubMedCrossRefGoogle Scholar
  213. 213.
    Sicinski P, Donaher JL, B. PS, Li T, Fazeli A, Gardner H, Haslam SZ, Bronson RT, Elledge SJ, Weinberg RA (1995) Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:621–630 PubMedCrossRefGoogle Scholar
  214. 214.
    Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY, Robker RL, Richards JS, McGinnis LK, Biggers JD, Eppig JJ, Bronson RT, Elledge SJ, Weinberg RA (1996) Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 384:470–474 PubMedCrossRefGoogle Scholar
  215. 215.
    Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, Leder P (1987) Coexpression of MMTV/v-Ha-Ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell 49:465–475 PubMedCrossRefGoogle Scholar
  216. 216.
    Slack JM (1995) Developmental biology of the pancreas. Development 121:1569–1580 PubMedGoogle Scholar
  217. 217.
    Slingerland J, Pagano M (2000) Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol 183:10–17 PubMedCrossRefGoogle Scholar
  218. 218.
    Slingerland JM, Hengst L, Pan CH, Alexander D, Stampfer MR, Reed SI (1994) A novel inhibitor of cyclin-Cdk activity detected in transforming growth factor beta-arrested epithelial cells. Mol Cell Biol 14:3683–3694 PubMedGoogle Scholar
  219. 219.
    Sotillo R, Dubus P, Martin J, de la Cueva E, Ortega S, Malumbres M, Barbacid M (2001a) Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors. EMBO J 20:6637–6647 PubMedCrossRefGoogle Scholar
  220. 220.
    Sotillo R, Garcia JF, Ortega S, Martin J, Dubus P, Barbacid M, Malumbres M (2001b) Invasive melanoma in Cdk4-targeted mice. Proc Natl Acad Sci USA 98:13312–13317 PubMedCrossRefGoogle Scholar
  221. 221.
    Sotillo R, Renner O, Dubus P, Ruiz-Cabello J, Martin-Caballero J, Barbacid M, Carnero A, Malumbres M (2005) Cooperation between Cdk4 and p27Kip1 in tumor development: a preclinical model to evaluate cell cycle inhibitors with therapeutic activity. Cancer Res 65:3846–3852 PubMedCrossRefGoogle Scholar
  222. 222.
    Stern B, Nurse P (1996) A quantitative model for the cdc2 control of S phase and mitosis in fission yeast. Trends Genet 12:345–350 PubMedCrossRefGoogle Scholar
  223. 223.
    Stewart TA, Pattengale PK, Leder P (1984) Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell 38:627–637 PubMedCrossRefGoogle Scholar
  224. 224.
    Strausfeld UP, Howell M, Descombes P, Chevalier S, Rempel RE, Adamczewski J, Maller JL, Hunt T, Blow JJ (1996) Both cyclin A and cyclin E have S-phase promoting (SPF) activity in Xenopus egg extracts. J Cell Sci 109:1555–1563 PubMedGoogle Scholar
  225. 225.
    Su TT, O'Farrell PH (1998) Size control: cell proliferation does not equal growth. Curr Biol 8: R687–689 Google Scholar
  226. 226.
    Sui L, Dong Y, Ohno M, Sugimoto K, Tai Y, Hando T, Tokuda M (2001) Implication of malignancy and prognosis of p27Kip1, Cyclin E, and Cdk2 expression in epithelial ovarian tumors. Gynecol Oncol 83:56–63 PubMedCrossRefGoogle Scholar
  227. 227.
    Sutterluty H, Chatelain E, Marti A, Wirbelauer C, Senften M, Muller U, Krek W (1999) p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol 1:207–214 PubMedCrossRefGoogle Scholar
  228. 228.
    Sweeney C, Murphy M, Kubelka M, Ravnik SE, Hawkins CF, Wolgemuth DJ, Carrington M (1996) A distinct cyclin A is expressed in germ cells in the mouse. Development 122:53–64 PubMedGoogle Scholar
  229. 229.
    Takizawa CG, Morgan DO (2000) Control of mitosis by changes in the subcellular location of cyclin B1-Cdk1 and Cdc25C. Curr Opin Cell Biol 12:658–665 PubMedCrossRefGoogle Scholar
  230. 230.
    Tanaka H, Kanagawa H (1997) Influence of combined activation treatments on the success of bovine nuclear transfer using young or aged oocytes. Anim Reprod Sci 49:113–123 PubMedCrossRefGoogle Scholar
  231. 231.
    Teixeira LT, Kiyokawa H, Peng XD, Christov KT, Frohman LA, Kineman RD (2000) p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation. Oncogene 19:1875–1884 PubMedCrossRefGoogle Scholar
  232. 232.
    Tetsu O, McCormick F (2003) Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 3:233–245 PubMedCrossRefGoogle Scholar
  233. 233.
    Tevosian SG, Paulson KE, Bronson R, Yee AS (1996) Expression of the E2F-1/DP-1 transcription factor in murine development. Cell Growth Differ 7:43–52 PubMedGoogle Scholar
  234. 234.
    Th'ng JP, Wright PS, Hamaguchi J, Lee MG, Norbury CJ, Nurse P, Bradbury EM (1990) The FT210 cell line is a mouse G2 phase mutant with a temperature-sensitive CDC2 gene product. Cell 63:313–324 PubMedCrossRefGoogle Scholar
  235. 235.
    Tong W, Pollard JW (2001) Genetic evidence for the interactions of cyclin D1 and p27Kip1 in mice. Mol Cell Biol 21:1319–1328 PubMedCrossRefGoogle Scholar
  236. 236.
    Toyoshima F, Moriguchi T, Wada A, Fukuda M, Nishida E (1998) Nuclear export of cyclin B1 and its possible role in the DNA damage-induced G2 checkpoint. EMBO J 17:2728–2735 PubMedCrossRefGoogle Scholar
  237. 237.
    Tsai LH, Harlow E, Meyerson M (1991) Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase. Nature 353:174–177 PubMedCrossRefGoogle Scholar
  238. 238.
    Tsai LH, Lees E, Faha B, Harlow E, Riabowol K (1993) The cdk2 kinase is required for the G1-to-S transition in mammalian cells. Oncogene 8:1593–602 PubMedGoogle Scholar
  239. 239.
    Tsukamoto AS, Grosschedl R, Guzman RC, Parslow T, Varmus HE (1988) Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 55:619–625 PubMedCrossRefGoogle Scholar
  240. 240.
    Tsutsui T, Hesabi B, Moons DS, Pandolfi PP, Hansel KS, Koff A, Kiyokawa H (1999) Targeted disruption of CDK4 delays cell cycle entry with enhanced p27Kip1 activity. Mol Cell Biol 19:7011–7019 PubMedGoogle Scholar
  241. 241.
    Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H (1999) p27Kip1 ubiquitination and degradation is regulated by the SCFSkp2 complex through phosphorylated Thr187 in p27. Curr Biol 9:661–664 PubMedCrossRefGoogle Scholar
  242. 242.
    Uchida T, Nakamura T, Hashimoto N, Matsuda T, Kotani K, Sakaue H, Kido Y, Hayashi Y, Nakayama KI, White MF, Kasuga M (2005) Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice. Nat Med 11:175–182 PubMedCrossRefGoogle Scholar
  243. 243.
    van den Heuvel S, Harlow E (1993) Distinct roles for cyclin-dependent kinases in cell cycle control. Science 262:2050–2054 PubMedCrossRefGoogle Scholar
  244. 244.
    Vial D, Oliver C, Jamur MC, Pastor MV, da Silva Trindade E, Berenstein E, Zhang J, Siraganian RP (2003) Alterations in granule matrix and cell surface of focal adhesion kinase-deficient mast cells. J Immunol 171:6178–6186 PubMedGoogle Scholar
  245. 245.
    Vlach J, Hennecke S, Amati B (1997) Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27Kip1. EMBO J 16:5334–5344 PubMedCrossRefGoogle Scholar
  246. 246.
    Wadler S (2002) Perspectives for cancer therapies with cdk2 inhibitors. Drug Res Updates 4:347–367 CrossRefGoogle Scholar
  247. 247.
    Weinstat-Saslow D, Merino MJ, Manrow RE, Lawrence JA, Bluth RF, Wittenbel KD, Simpson JF, Page DL, Steeg PS (1995) Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions. Nat Med 1:1257–1260 PubMedCrossRefGoogle Scholar
  248. 248.
    Welcker M, Clurman B (2005) Cell cycle: how cyclin E got its groove back. Curr Biol 15:R810–812 PubMedCrossRefGoogle Scholar
  249. 249.
    Williams BO, Morgenbesser SD, DePinho RA, Jacks T (1994a) Tumorigenic and developmental effects of combined germ-line mutations in Rb and p53. Cold Spring Harb Symp Quant Biol 59:449–457 PubMedGoogle Scholar
  250. 250.
    Williams BO, Remington L, Albert DM, Mukai S, Bronson RT, Jacks T (1994b) Cooperative tumorigenic effects of germline mutations in Rb and p53. Nat Genet 7:480–484 PubMedCrossRefGoogle Scholar
  251. 251.
    Wittenberg C, Sugimoto K, Reed SI (1990) G1-specific cyclins of S. cerevisiae: cell cycle periodicity, regulation by mating pheromone, and association with the p34CDC28 protein kinase. Cell 62:225–237 PubMedCrossRefGoogle Scholar
  252. 252.
    Wu CL, Zukerberg LR, Ngwu C, Harlow E, Lees JA (1995) In vivo association of E2F and DP family proteins. Mol Cell Biol 15:2536–2546 PubMedGoogle Scholar
  253. 253.
    Wu L, de Bruin A, Saavedra HI, Starovic M, Trimboli A, Yang Y, Opavska J, Wilson P, Thompson JC, Ostrowski MC, Rosol TJ, Woollett LA, Weinstein M, Cross JC, Robinson ML, Leone G (2003) Extra-embryonic function of Rb is essential for embryonic development and viability. Nature 421:942–947 PubMedCrossRefGoogle Scholar
  254. 254.
    Xiong Y, Connolly T, Futcher B, Beach D (1991) Human D-type cyclin. Cell 65:691–699 PubMedCrossRefGoogle Scholar
  255. 255.
    Xiong Y, Menninger J, Beach D, Ward DC (1992) Molecular cloning and chromosomal mapping of CCND genes encoding human D-type cyclins. Genomics 13:575–584 PubMedCrossRefGoogle Scholar
  256. 256.
    Yang J, Bardes ES, Moore JD, Brennan J, Powers MA, Kornbluth S (1998) Control of cyclin B1 localization through regulated binding of the nuclear export factor CRM1. Genes Dev 12:2131–2143 PubMedCrossRefGoogle Scholar
  257. 257.
    Yang R, Morosetti R, Koeffler HP (1997) Characterization of a second human cyclin A that is highly expressed in testis and in several leukemic cell lines. Cancer Res 57:913–920 PubMedGoogle Scholar
  258. 258.
    Ye X, Zhu C, Harper JW (2001) A premature-termination mutation in the Mus musculus cyclin-dependent kinase 3 gene. Proc Natl Acad Sci USA 98:1682–1686 PubMedCrossRefGoogle Scholar
  259. 259.
    Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, Song KH, Yoo SJ, Kang MI, Cha BY, Lee KW, Son HY, Kang SK, Kim HS, Lee IK, Bonner-Weir S (2003) Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab 88:2300–2308 PubMedCrossRefGoogle Scholar
  260. 260.
    Yu Q, Geng Y, Sicinski P (2001) Specific protection against breast cancers by cyclin D1 ablation. Nature 411:1017–1021 PubMedCrossRefGoogle Scholar
  261. 261.
    Yuan L, Liu JG, Zhao J, Brundell E, Daneholt B, Hoog C (2000) The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Mol Cell 5:73–83 PubMedCrossRefGoogle Scholar
  262. 262.
    Zhang Y, Chellappan SP (1995) Cloning and characterization of human DP2, a novel dimerization partner of E2F. Oncogene 10:2085–2093 PubMedGoogle Scholar
  263. 263.
    Zimmet J, Ravid K (2000) Polyploidy: occurrence in nature, mechanisms, and significance for the megakaryocyte-platelet system. Exp Hematol 28:3–16 PubMedCrossRefGoogle Scholar
  264. 264.
    Zimmet JM, Ladd D, Jackson CW, Stenberg PE, Ravid K (1997) A role for cyclin D3 in the endomitotic cell cycle. Mol Cell Biol 17:7248–7259 PubMedGoogle Scholar
  265. 265.
    Zindy F, den Besten W, Chen B, Rehg JE, Latres E, Barbacid M, Pollard JW, Sherr CJ, Cohen PE, Roussel MF (2001) Control of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors p18Ink4c and p19Ink4d. Mol Cell Biol 21:3244–3255 PubMedCrossRefGoogle Scholar
  266. 266.
    Zindy F, Soares H, Herzog K-H, Morgan J, Sherr CJ, Roussel MF (1997) Expression of INK4 inhibitors of cyclin D-dependent kinases during mouse brain development. Cell Growth Differ 8:1139–1150 PubMedGoogle Scholar
  267. 267.
    Zindy F, van Deursen J, Grosveld G, Sherr CJ, Roussel MF (2000) INK4d-deficient mice are fertile despite testicular atrophy. Mol Cell Biol 20:372–378 PubMedCrossRefGoogle Scholar
  268. 268.
    Zou L, Stillman B (2000) Assembly of a complex containing Cdc45p, replication protein A, and Mcm2p at replication origins controlled by S-phase cyclin-dependent kinases and Cdc7p-Dbf4p kinase. Mol Cell Biol 20:3086–3096 PubMedCrossRefGoogle Scholar
  269. 269.
    Zou X, Ray D, Aziyu A, Christov K, Boiko AD, Gudkov AV, Kiyokawa H (2002) Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to Arf/p53-independent senescence. Genes Dev 16:2923–2934 PubMedCrossRefGoogle Scholar
  270. 270.
    Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward N, Dracopoli NC (1996) Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 12:97–99. PubMedCrossRefGoogle Scholar

Authors and Affiliations

  1. 1.National Cancer InstituteMouse Cancer Genetics Program, NCI-Frederick, Bldg. 560/22-56FrederickUSA
  2. 2.Department of Zoology, Faculty of ScienceUniversity of AlexandriaAlexandriaEgypt

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