Receptors, Signaling Pathways, Cell Cycle, and DNA Damage Repair

  • Philip T. Cagle
Part of the Molecular Pathology Library book series (MPLB, volume 1)


Ligands are extracellular messenger molecules such as growth factors, inflammatory cytokines, and hormones that bind to specific receptors on the cell surface (i.e., growth factor receptors, cytokine receptors, and hormone receptors). Binding of the ligands to their receptors causes activation of second messengers in the cytosol and eventually activation of nuclear transcription factors (Transcription factors are discussed in Chapter 1.) The transcription factors then direct the transcription of a gene product as a result of the extracellular message (e.g., a growth factor may stimulate a growth factor receptor on the cell surface, causing activation of second messengers that eventually cause a transcription factor to cause transcription of a protein involved in cell growth). This cascade or activation and inactivation of protein messengers from the cell surface receptors through proteins in the cytosol to the transcription factors in the nucleus is known as signal transduction. The series of steps that occurs during this process is called the signal transduction pathway or signaling pathway. Much of the activation and inactivation of proteins in signaling pathways occurs through reversible phosphorylation of tyrosine, serine, or threonine in the pathway proteins (see Chapter 1).


Cell Cycle Adenomatous Polyposis Coli Nijmegen Breakage Syndrome Curr Opin Cell Biol Semin Cancer Biol 
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  1. 1.
    Williams LT, Escobedo JA, Fantl WJ, et al. Interactions of growth factor receptors with cytoplasmic signaling molecules. Cold Spring Harb Symp Quant Biol 1991;56:243–250.PubMedGoogle Scholar
  2. 2.
    Fantl WJ, Escobedo JA, Martin GA, et al. Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways. Cell 1992;69:413–423.PubMedCrossRefGoogle Scholar
  3. 3.
    Hunter T, Lindberg RA, Middlemas DS, et al. Receptor protein tyrosine kinases and phosphatases. Cold Spring Harb Symp Quant Biol 1992;57:25–41.PubMedGoogle Scholar
  4. 4.
    Fantl WJ, Johnson DE, Williams LT. Signalling by receptor tyrosine kinases. Annu Rev Biochem 1993;62:453–481.PubMedGoogle Scholar
  5. 5.
    Johnson GL, Vaillancourt RR. Sequential protein kinase reactions controlling cell growth and differentiation. Curr Opin Cell Biol 1994;6:230–238.PubMedCrossRefGoogle Scholar
  6. 6.
    van der Geer P, Hunter T, Lindberg RA. Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol 1994;10:251–337.PubMedCrossRefGoogle Scholar
  7. 7.
    Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000;103:211–225.PubMedCrossRefGoogle Scholar
  8. 8.
    Gavi S, Shumay E, Wang HY, Malbon CC. G-protein-coupled receptors and tyrosine kinases: crossroads in cell signaling and regulation. Trends Endocrinol Metab 2006;17:48–54.PubMedCrossRefGoogle Scholar
  9. 9.
    Li E, Hristova K. Role of receptor tyrosine kinase transmembrane domains in cell signaling and human pathologies. Biochemistry 2006;45:6241–6251.PubMedCrossRefGoogle Scholar
  10. 10.
    Perona R. Cell signalling: growth factors and tyrosine kinase receptors. Clin Transl Oncol 2006;8:77–82.PubMedCrossRefGoogle Scholar
  11. 11.
    Tiganis T. Protein tyrosine phosphatases: dephosphorylating the epidermal growth factor receptor. IUBMB Life 2002;53:3–14.PubMedCrossRefGoogle Scholar
  12. 12.
    Jorissen RN, Walker F, Pouliot N, et al. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 2003;284:31–53.PubMedCrossRefGoogle Scholar
  13. 13.
    Bazley LA, Gullick WJ. The epidermal growth factor receptor family. Endocr Relat Cancer 2005;12Suppl 1:S17–S27.PubMedCrossRefGoogle Scholar
  14. 14.
    Normanno N, Bianco C, Strizzi L, et al. The ErbB receptors and their ligands in cancer: an overview. Curr Drug Targets 2005;6:243–257.PubMedCrossRefGoogle Scholar
  15. 15.
    Zaczek A, Brandt B, Bielawski KP. The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches. Histol Histopathol 2005;20:1005–1015.PubMedGoogle Scholar
  16. 16.
    Warren CM, Landgraf R. Signaling through ERBB receptors: multiple layers of diversity and control. Cell Signal 2006;18:923–933.PubMedCrossRefGoogle Scholar
  17. 17.
    Bagrodia S, Derijard B, Davis RJ, Cerione RA. Cdc42 and PAKmediated signaling leads to Jun kinase and p38 mitogen-activated protein kinase activation. J Biol Chem 1995;270:27995–27998.PubMedCrossRefGoogle Scholar
  18. 18.
    Xia Z, Dickens M, Raingeaud J, et al. Opposing effects of ERK and JNKp38 MAP kinases on apoptosis. Science 1995;270:1326–1331.PubMedCrossRefGoogle Scholar
  19. 19.
    Ichijo H, Nishida E, Irie K, et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997;275:90–94.PubMedCrossRefGoogle Scholar
  20. 20.
    Wilkinson MG, Millar JB. SAPKs and transcription factors do the nucleocytoplasmic tango. Genes Dev 1998;12:1391–1397.PubMedCrossRefGoogle Scholar
  21. 21.
    Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell 2000;103:239–252.PubMedCrossRefGoogle Scholar
  22. 22.
    Wada T, Penninger JM. Mitogen-activated protein kinases in apoptosis regulation. Oncogene 2004;23:2838–2849.PubMedCrossRefGoogle Scholar
  23. 23.
    Bradham C, McClay DR. p38 MAPK in Development and Cancer. Cell Cycle 2006;5:824–828.PubMedGoogle Scholar
  24. 24.
    MacCorkle RA, Tan TH. Mitogen-activated protein kinases in cell-cycle control. Cell Biochem Biophys 2005;43:451–461.PubMedCrossRefGoogle Scholar
  25. 25.
    Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 2006;24:21–44.PubMedCrossRefGoogle Scholar
  26. 26.
    Magnuson NS, Beck T, Vahidi H, et al. The Raf-1 serine/threonine protein kinase. Semin Cancer Biol 1994;5:247–253.PubMedGoogle Scholar
  27. 27.
    Williams NG, Roberts TM. Signal transduction pathways involving the Raf proto-oncogene. Cancer Metastasis Rev 1994;13:105–116.PubMedCrossRefGoogle Scholar
  28. 28.
    Burgering BM, Bos JL. Regulation of Ras-mediated signalling: more than one way to skin a cat. Trends Biochem Sci 1995;20:18–22.PubMedCrossRefGoogle Scholar
  29. 29.
    Morrison DK. Mechanisms regulating Raf-1 activity in signal transduction pathways. Mol Reprod Dev 1995;42:507–514.PubMedCrossRefGoogle Scholar
  30. 30.
    Morrison DK, Cutler RE. The complexity of Raf-1 regulation. Curr Opin Cell Biol 1997;9:174–179.PubMedCrossRefGoogle Scholar
  31. 31.
    Dhillon AS, Kolch W. Untying the regulation of the Raf-1 kinase. Arch Biochem Biophys 2002;404:3–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Bernards A, Settleman J. GAP control: regulating the regulators of small GTPases. Trends Cell Biol 2004;14:377–385.PubMedCrossRefGoogle Scholar
  33. 33.
    Bernards A, Settleman J. GAPs in growth factor signalling. Growth Factors 2005;23:143–149.PubMedCrossRefGoogle Scholar
  34. 34.
    Chan A. Teaching resources. Ras-MAPK pathways. Sci STKE 2005;2005(271):tr5.PubMedCrossRefGoogle Scholar
  35. 35.
    Hancock JF, Parton RG. Ras plasma membrane signalling platforms. Biochem J 2005;389 (Pt 1):1–11.PubMedCrossRefGoogle Scholar
  36. 36.
    Kranenburg O. The KRAS oncogene: past, present, and future. Biochim Biophys Acta 2005;1756:81–82.PubMedGoogle Scholar
  37. 37.
    McCudden CR, Hains MD, Kimple RJ, et al. G-protein signaling: back to the future. Cell Mol Life Sci 2005;62:551–577.PubMedCrossRefGoogle Scholar
  38. 38.
    Mitin N, Rossman KL, Der CJ. Signaling interplay in Ras superfamily function. Curr Biol 2005;15:R563–574.PubMedCrossRefGoogle Scholar
  39. 39.
    Philips MR. Compartmentalized signalling of Ras. Biochem Soc Trans 2005;33 (Pt 4):657–661.PubMedCrossRefGoogle Scholar
  40. 40.
    Wennerberg K, Rossman KL, Der CJ. The Ras superfamily at a glance. J Cell Sci 2005;118 (Pt 5):843–846.PubMedCrossRefGoogle Scholar
  41. 41.
    Mor A, Philips MR. Compartmentalized Ras/MAPK signaling. Annu Rev Immunol 2006;24:771–800.PubMedCrossRefGoogle Scholar
  42. 42.
    Pellegrini S, Dusanter-Fourt I. The structure, regulation and function of the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs). Eur J Biochem 1997;248:615–633.PubMedCrossRefGoogle Scholar
  43. 43.
    Liu KD, Gaffen SL, Goldsmith MA. JAK/STAT signaling by cytokine receptors. Curr Opin Immunol 1998;10:271–278.PubMedCrossRefGoogle Scholar
  44. 44.
    Shuai K. The STAT family of proteins in cytokine signaling. Prog Biophys Mol Biol 1999;71:405–422.PubMedCrossRefGoogle Scholar
  45. 45.
    Boudny V, Kovarik J. JAK/STAT signaling pathways and cancer. Janus kinases/signal transducers and activators of transcription. Neoplasma 2002;49:349–355.PubMedGoogle Scholar
  46. 46.
    Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 2002;285:1–24.PubMedCrossRefGoogle Scholar
  47. 47.
    O’Shea JJ, Gadina M, Schreiber RD. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 2002;109Suppl:S121–S131.PubMedCrossRefGoogle Scholar
  48. 48.
    Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci 2004;117 (Pt 8):1281–1283.PubMedCrossRefGoogle Scholar
  49. 49.
    Hebenstreit D, Horejs-Hoeck J, Duschl A. JAK/STAT-dependent gene regulation by cytokines. Drug News Perspect 2005;18:243–249.PubMedCrossRefGoogle Scholar
  50. 50.
    Lutz M, Knaus P. Integration of the TGF-beta pathway into the cellular signalling network. Cell Signal 2002;14:977–988.PubMedCrossRefGoogle Scholar
  51. 51.
    Mehra A, Wrana JL. TGF-beta and the Smad signal transduction pathway. Biochem Cell Biol 2002;80:605–622.PubMedCrossRefGoogle Scholar
  52. 52.
    Cohen MM Jr. TGF beta/Smad signaling system and its pathologic correlates. Am J Med Genet A 2003;116:1–10.CrossRefGoogle Scholar
  53. 53.
    Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003;425:577–584.PubMedCrossRefGoogle Scholar
  54. 54.
    Chin D, Boyle GM, Parsons PG, Coman WB. What is transforming growth factor-beta (TGF-beta)? Br J Plast Surg 2004;57:215–221.PubMedCrossRefGoogle Scholar
  55. 55.
    ten Dijke P, Hill CS. New insights into TGF-beta-Smad signalling. Trends Biochem Sci 2004;29:265–273.PubMedCrossRefGoogle Scholar
  56. 56.
    Feng XH, Derynck R. Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol 2005;21:659–693.PubMedCrossRefGoogle Scholar
  57. 57.
    Park SH. Fine tuning and cross-talking of TGF-beta signal by inhibitory Smads. J Biochem Mol Biol 2005;38:9–16.PubMedGoogle Scholar
  58. 58.
    Massague J, Seoane J, Wotton D. Smad transcription factors. Genes Dev 2005;19:2783–2810.PubMedCrossRefGoogle Scholar
  59. 59.
    Massague J, Gomis RR. The logic of TGFbeta signaling. FEBS Lett 2006;580:2811–2820.PubMedCrossRefGoogle Scholar
  60. 60.
    Gumbiner BM. Signal transduction of beta-catenin. Curr Opin Cell Biol 1995;7:634–640.PubMedCrossRefGoogle Scholar
  61. 61.
    Shimizu H, Julius MA, Giarre M, et al. Transformation by Wnt family proteins correlates with regulation of betacatenin. Cell Growth Differ 1997;8:1349–1358.PubMedGoogle Scholar
  62. 62.
    Boutros M, Mlodzik M. Dishevelled: at the crossroads of divergent intracellular signaling pathways. Mech Dev 1999;83:27–37.PubMedCrossRefGoogle Scholar
  63. 63.
    Miller JR, Hocking AM, Brown JD, Moon RT. Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene 1999;18:7860–7872.PubMedCrossRefGoogle Scholar
  64. 64.
    Hinoi T, Yamamoto H, Kishida M, et al. Complex formation of adenomatous polyposis coli gene product and axin facilitates glycogen synthase kinase-3 beta-dependent phosphorylation of beta-catenin and downregulates betacatenin. J Biol Chem 2000;275:34399–34406.PubMedCrossRefGoogle Scholar
  65. 65.
    Polakis P. Wnt signaling and cancer. Genes Dev 2000;14:1837–1851.PubMedGoogle Scholar
  66. 66.
    Doble BW, Woodgett JR. GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 2003;116:1175–1186.PubMedCrossRefGoogle Scholar
  67. 67.
    Lee E, Salic A, Kruger R, et al. The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol 2003;1:E10.PubMedCrossRefGoogle Scholar
  68. 68.
    van Es JH, Barker N, Clevers H. You Wnt some, you lose some: oncogenes in the Wnt signaling pathway. Curr Opin Genet Dev 2003;13:28–33.PubMedCrossRefGoogle Scholar
  69. 69.
    Veeman MT, Axelrod JD, Moon RT. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell 2003;5:367–377.PubMedCrossRefGoogle Scholar
  70. 70.
    Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004;20:781–810.PubMedCrossRefGoogle Scholar
  71. 71.
    Malbon CC. Frizzleds: new members of the superfamily of G-protein-coupled receptors. Front Biosci 2004;9:1048–1058.PubMedCrossRefGoogle Scholar
  72. 72.
    Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 2004;303:1483–1487.PubMedCrossRefGoogle Scholar
  73. 73.
    Tolwinski NS, Wieschaus E. Rethinking WNT signaling. Trends Genet 2004;20:177–181.PubMedCrossRefGoogle Scholar
  74. 74.
    Bejsovec A. Wnt pathway activation: new relations and locations. Cell 2005;120:11–14.PubMedGoogle Scholar
  75. 75.
    Senda T, Shimomura A, Iizuka-Kogo A. Adenomatous polyposis coli (Apc) tumor suppressor gene as a multifunctional gene. Anat Sci Int 2005;80:121–131.PubMedCrossRefGoogle Scholar
  76. 76.
    Takada R, Hijikata H, Kondoh H, Takada S. Analysis of combinatorial effects of Wnts and Frizzleds on betacatenin/armadillo stabilization and Dishevelled 77 phosphorylation. Genes Cells 2005;10:919–928.PubMedCrossRefGoogle Scholar
  77. 77.
    Cadigan KM, Liu YI. Wnt signaling: complexity at the surface. J Cell Sci 2006;119:395–402.PubMedCrossRefGoogle Scholar
  78. 78.
    Kikuchi A, Kishida S, Yamamoto H. Regulation of Wnt signaling by protein-protein interaction and posttranslational modifications. Exp Mol Med 2006;38:1–10.PubMedGoogle Scholar
  79. 79.
    Malbon CC, Wang HY. Dishevelled: a mobile scaffold catalyzing development. Curr Top Dev Biol 2006;72:153–166.PubMedCrossRefGoogle Scholar
  80. 80.
    Pongracz JE, Stockley RA. Wnt signalling in lung development and diseases. Respir Res 2006;7:15.PubMedCrossRefGoogle Scholar
  81. 81.
    Tian Q. Proteomic exploration of the Wnt/beta-catenin pathway. Curr Opin Mol Ther 2006;8:191–197PubMedGoogle Scholar
  82. 82.
    Franke TF, Kaplan DR, Cantley LC. PI3K: downstream AKTion blocks apoptosis. Cell 1997;88:435–437.PubMedCrossRefGoogle Scholar
  83. 83.
    Wymann MP, Pirola L. Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta 1998;1436:127–150.PubMedGoogle Scholar
  84. 84.
    Krasilnikov MA. Phosphatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation. Biochemistry (Mosc) 2000;65:59–67.Google Scholar
  85. 85.
    Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655–1657.PubMedCrossRefGoogle Scholar
  86. 86.
    Franke TF, Hornik CP, Segev L, et al. PI3K/Akt and apoptosis: size matters. Oncogene 2003;22:8983–8998.PubMedCrossRefGoogle Scholar
  87. 87.
    Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2003;2:339–345.PubMedGoogle Scholar
  88. 88.
    Asnaghi L, Bruno P, Priulla M, Nicolin A. mTOR: a protein kinase switching between life and death. Pharmacol Res 2004;50:545–549.PubMedCrossRefGoogle Scholar
  89. 89.
    Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis 2004;9:667–676.PubMedCrossRefGoogle Scholar
  90. 90.
    Henson ES, Gibson SB. Surviving cell death through epidermal growth factor (EGF) signal transduction pathways: Implications for cancer therapy. Cell Signal 2006 May 24; [Epub ahead of print].Google Scholar
  91. 90.
    Liang Y, Zhou Y, Shen P. NF-kappaB and its regulation on the immune system. Cell Mol Immunol 2004;1:343–350.PubMedGoogle Scholar
  92. 92.
    Xiao W. Advances in NF-kappaB signaling transduction and transcription. Cell Mol Immunol 2004;1:425–435.PubMedGoogle Scholar
  93. 93.
    Courtois G. The NF-kappaB signaling pathway in human genetic diseases. Cell Mol Life Sci 2005;62:1682–1691.PubMedCrossRefGoogle Scholar
  94. 94.
    Moynagh PN. The NF-kappaB pathway. J Cell Sci 2005;118 (Pt 20):4589–4592.PubMedCrossRefGoogle Scholar
  95. 95.
    Zingarelli B. Nuclear factor-kappaB. Crit Care Med 2005;33(12 Suppl):S414–S416.PubMedCrossRefGoogle Scholar
  96. 96.
    Bubici C, Papa S, Pham CG, et al. The NF-kappaB-mediated control of ROS and JNK signaling. Histol Histopathol 2006;21:69–80.PubMedGoogle Scholar
  97. 97.
    Campbell KJ, Perkins ND. Regulation of NF-kappaB function. Biochem Soc Symp 2006;(73):165–180.Google Scholar
  98. 98.
    Hoffmann A, Baltimore D. Circuitry of nuclear factor kappaB signaling. Immunol Rev 2006;210:171–186.PubMedCrossRefGoogle Scholar
  99. 99.
    Piva R, Belardo G, Santoro MG. NF-kappaB: a stress-regulated switch for cell survival. Antioxid Redox Signal 2006;8:478–486.PubMedCrossRefGoogle Scholar
  100. 100.
    Vermeulen L, Vanden Berghe W, Haegeman G. Regulation of NF-kappaB transcriptional activity. Cancer Treat Res 2006;130:89–102.PubMedCrossRefGoogle Scholar
  101. 101.
    Karin M. The beginning of the end: IkappaB kinase (IKK) and NF-kappaB activation. J Biol Chem 1999;274:27339–27342.PubMedCrossRefGoogle Scholar
  102. 102.
    Karin M. How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex. Oncogene 1999;18:6867–6874.PubMedCrossRefGoogle Scholar
  103. 103.
    Rothwarf DM, Karin M. The NF-kappa B activation pathway: a paradigm in information transfer from membrane to nucleus. Sci STKE 1999;1999:RE1.PubMedCrossRefGoogle Scholar
  104. 104.
    Senftleben U, Karin M. The IKK/NF-kappa B pathway. Crit Care Med 2002;30(1 Suppl):S18–S26.CrossRefGoogle Scholar
  105. 105.
    Hayden MS, Ghosh S. Signaling to NF-kappaB. Genes Dev 2004;18:2195–2224.PubMedCrossRefGoogle Scholar
  106. 106.
    Viatour P, Merville MP, Bours V, Chariot A. Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends Biochem Sci 2005;30:43–52.PubMedCrossRefGoogle Scholar
  107. 107.
    Gloire G, Dejardin E, Piette J. Extending the nuclear roles of IkappaB kinase subunits. Biochem Pharmacol 2006 Jul 15; [Epub ahead of print].Google Scholar
  108. 108.
    Kalderon D. Similarities between the Hedgehog and Wnt signaling pathways. Trends Cell Biol 2002;12:523–531.PubMedCrossRefGoogle Scholar
  109. 109.
    Mullor JL, Sanchez P, Altaba AR. Pathways and consequences: Hedgehog signaling in human disease. Trends Cell Biol 2002;12:562–569.PubMedCrossRefGoogle Scholar
  110. 110.
    Cohen MM Jr. The hedgehog signaling network. Am J Med Genet A 2003;123:5–28.CrossRefGoogle Scholar
  111. 111.
    McMahon AP, Ingham PW, Tabin CJ. Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol 2003;53:1–114.PubMedCrossRefGoogle Scholar
  112. 112.
    Wetmore C. Sonic hedgehog in normal and neoplastic proliferation: insight gained from human tumors and animal models. Curr Opin Genet Dev 2003;13:34–42.PubMedCrossRefGoogle Scholar
  113. 113.
    Lum L, Beachy PA. The Hedgehog response network: sensors, switches, and routers. Science 2004;304:1755–1759.PubMedCrossRefGoogle Scholar
  114. 114.
    Ogden SK, Ascano M Jr, Stegman MA, Robbins DJ. Regulation of Hedgehog signaling: a complex story. Biochem Pharmacol 2004;67:805–814.PubMedCrossRefGoogle Scholar
  115. 115.
    Yu TC, Miller SJ. The hedgehog pathway: revisited. Dermatol Surg 2004;30:583–584.PubMedCrossRefGoogle Scholar
  116. 116.
    Neumann CJ. Hedgehogs as negative regulators of the cell cycle. Cell Cycle 2005;4:1139–1140.PubMedGoogle Scholar
  117. 117.
    Baron M, Aslam H, Flasza M, et al. Multiple levels of Notch signal regulation (review). Mol Membr Biol 2002;19:27–38.PubMedCrossRefGoogle Scholar
  118. 118.
    Baron M. An overview of the Notch signalling pathway. Semin Cell Dev Biol 2003;14:113–119.PubMedCrossRefGoogle Scholar
  119. 119.
    Collins BJ, Kleeberger W, Ball DW. Notch in lung development and lung cancer. Semin Cancer Biol 2004;14:357–364.PubMedCrossRefGoogle Scholar
  120. 120.
    Hansson EM, Lendahl U, Chapman G. Notch signaling in development and disease. Semin Cancer Biol 2004;14:320–328.PubMedCrossRefGoogle Scholar
  121. 121.
    Bianchi S, Dotti MT, Federico A. Physiology and pathology of notch signalling system. J Cell Physiol 2006;207:300–308.PubMedCrossRefGoogle Scholar
  122. 122.
    Wilson A, Radtke F. Multiple functions of Notch signaling in self-renewing organs and cancer. FEBS Lett 2006;580:2860–2868.PubMedCrossRefGoogle Scholar
  123. 123.
    Hartwell LH, Weinert TA. Checkpoints: controls that ensure the order of cell cycle events. Science 1989;246:629–634.PubMedCrossRefGoogle Scholar
  124. 124.
    Pardee AB. G1 events and regulation of cell proliferation. Science 1989;246:603–608.PubMedCrossRefGoogle Scholar
  125. 125.
    Kastan MB, Kuerbitz SJ. Control of G1 arrest after DNA damage. Environ Health Perspect 1993;101Suppl 5:55–58.PubMedCrossRefGoogle Scholar
  126. 126.
    Sherr CJ. G1 phase progression: cycling on cue. Cell 1994;79:551–555.PubMedCrossRefGoogle Scholar
  127. 127.
    Elledge SJ. Cell cycle checkpoints: preventing an identity crisis. Science 1996;274:1664–1672.PubMedCrossRefGoogle Scholar
  128. 128.
    Sanchez I, Dynlacht BD. Transcriptional control of the cell cycle. Curr Opin Cell Biol 1996;8:318–324.PubMedCrossRefGoogle Scholar
  129. 129.
    O’Connor PM. Mammalian G1 and G2 phase checkpoints. Cancer Surv 1997;29:151–182.PubMedGoogle Scholar
  130. 130.
    Mercer WE. Checking on the cell cycle. J Cell Biochem Suppl 1998;30–31:50–4.PubMedCrossRefGoogle Scholar
  131. 131.
    Weinert T. DNA damage checkpoints update: getting molecular. Curr Opin Genet Dev 1998;8:185–193.PubMedCrossRefGoogle Scholar
  132. 132.
    Johnson DG, Walker CL. Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol 1999;39:295–312.PubMedCrossRefGoogle Scholar
  133. 133.
    Clarke DJ, Gimenez-Abian JF. Checkpoints controlling mitosis. Bioessays 2000;22:351–363.PubMedCrossRefGoogle Scholar
  134. 134.
    Nyberg KA, Michelson RJ, Putnam CW, Weinert TA. Toward maintaining the genome: DNA damage and replication checkpoints. Annu Rev Genet 2002;36:617–656.PubMedCrossRefGoogle Scholar
  135. 135.
    Shreeram S, Blow JJ. The role of the replication licensing system in cell proliferation and cancer. Prog Cell Cycle Res 2003;5:287–293.PubMedGoogle Scholar
  136. 136.
    Lisby M, Rothstein R. DNA damage checkpoint and repair centers. Curr Opin Cell Biol 2004;16:328–334.PubMedCrossRefGoogle Scholar
  137. 137.
    Lukas J, Lukas C, Bartek J. Mammalian cell cycle checkpoints: signalling pathways and their organization in space and time. DNA Repair (Amst) 2004;3:997–1007.CrossRefGoogle Scholar
  138. 138.
    Stark GR, Taylor WR. Analyzing the G2/M checkpoint. Methods Mol Biol 2004;280:51–82.PubMedGoogle Scholar
  139. 139.
    Branzei D, Foiani M. The DNA damage response during DNA replication. Curr Opin Cell Biol 2005;17:568–575.PubMedCrossRefGoogle Scholar
  140. 140.
    Macaluso M, Montanari M, Cinti C, Giordano A. Modulation of cell cycle components by epigenetic and genetic events. Semin Oncol 2005;32:452–457.PubMedCrossRefGoogle Scholar
  141. 141.
    Musgrove EA. Cyclins: roles in mitogenic signaling and oncogenic transformation. Growth Factors 2006;24:13–19.PubMedCrossRefGoogle Scholar
  142. 142.
    Niida H, Nakanishi M. DNA damage checkpoints in mammals. Mutagenesis 2006;21:3–9.PubMedCrossRefGoogle Scholar
  143. 143.
    Burtelow MA, Roos-Mattjus PM, Rauen M, et al. Reconstitution and molecular analysis of the hRad9-hHus1-hRad1 (9-1-1) DNA damage responsive checkpoint complex. J Biol Chem 2001;276:25903–25909.PubMedCrossRefGoogle Scholar
  144. 144.
    Bao S, Lu T, Wang X, et al. Disruption of the Rad9/Rad1/Hus1 (9-1-1) complex leads to checkpoint signaling and replication defects. Oncogene 2004;23:5586–5593.PubMedCrossRefGoogle Scholar
  145. 145.
    Parrilla-Castellar ER, Arlander SJ, Karnitz L. Dial 9-1-1 for DNA damage: the Rad9-Hus1-Rad1 (9-1-1) clamp complex. DNA Repair (Amst) 2004;3:1009–1014.CrossRefGoogle Scholar
  146. 146.
    Majka J, Burgers PM. unction of Rad17/Mec3/Ddc1 and its partial complexes in the DNA damage checkpoint. DNA Repair (Amst) 2005;4:1189–1194.CrossRefGoogle Scholar
  147. 147.
    van Vugt MA, Medema RH. Checkpoint adaptation and recovery: back with Polo after the break. Cell Cycle 2004;3:1383–1386.PubMedGoogle Scholar
  148. 148.
    van Vugt MA, Bras A, Medema RH. Restarting the cell cycle when the checkpoint comes to a halt. Cancer Res 2005;65:7037–7040.PubMedCrossRefGoogle Scholar
  149. 149.
    Pardee AB. A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci USA 1974;71:1286–1290.PubMedCrossRefGoogle Scholar
  150. 150.
    Campisi J, Medrano EE, Morro G, Pardee AB. Restriction point control of cell growth by a labile protein: evidence for increased stability in transformed cells. Proc Natl Acad Sci USA 1982;79:436–440.PubMedCrossRefGoogle Scholar
  151. 151.
    Blagosklonny MV, Pardee AB. The restriction point of the cell cycle. Cell Cycle 2002;1:103–110.PubMedGoogle Scholar
  152. 152.
    Boonstra J. Progression through the G1-phase of the ongoing cell cycle. J Cell Biochem 2003;90:244–252.PubMedCrossRefGoogle Scholar
  153. 153.
    Baldin V, Lukas J, Marcote MJ, et al. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev 1993;7:812–821.PubMedCrossRefGoogle Scholar
  154. 154.
    Dowdy SF, Hinds PW, Louie K, et al. Physical interaction of the retinoblastoma protein with human D cyclins. Cell 1993;73:499–511.PubMedCrossRefGoogle Scholar
  155. 155.
    Kato J, Matsushime H, Hiebert SW, et al. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev 1993;7:331–342.PubMedCrossRefGoogle Scholar
  156. 156.
    Sewing A, Burger C, Brusselbach S, et al. Human cyclin D1 encodes a labile nuclear protein whose synthesis is directly induced by growth factors and suppressed by cyclic AMP. J Cell Sci 1993;104:545–555.PubMedGoogle Scholar
  157. 157.
    Lukas J, Muller H, Bartkova J, et al. DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell’s requirement for cyclin D1 function in G1. J Cell Biol 1994;125:625–638.PubMedCrossRefGoogle Scholar
  158. 158.
    Xiao ZX, Ginsberg D, Ewen M, Livingston DM. Regulation of the retinoblastoma protein-related protein p107 by G1 cyclin-associated kinases. Proc Natl Acad Sci USA 1996;93:4633–4637.PubMedCrossRefGoogle Scholar
  159. 159.
    Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta 2002;1602:73–87.PubMedGoogle Scholar
  160. 160.
    El-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993;75:817–825.PubMedCrossRefGoogle Scholar
  161. 161.
    Polyak K, Kato JY, Solomon MJ, et al. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev 1994;8:9–22.PubMedCrossRefGoogle Scholar
  162. 162.
    Biggs JR, Kraft AS. Inhibitors of cyclin-dependent kinase and cancer. J Mol Med 1995;73:509–514.PubMedCrossRefGoogle Scholar
  163. 163.
    Datto MB, Li Y, Panus JF, et al. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci USA 1995;92:5545–5549.PubMedCrossRefGoogle Scholar
  164. 164.
    Datto MB, Yu Y, Wang XF. Functional analysis of the transforming growth factor beta responsive elements in the WAF1/Cip1/p21 promoter. J Biol Chem 1995;270:28623–28628.PubMedCrossRefGoogle Scholar
  165. 165.
    Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 1995;83:993–1000.PubMedCrossRefGoogle Scholar
  166. 166.
    Yeudall WA, Jakus J. Cyclin kinase inhibitors add a new dimension to cell cycle control. Eur J Cancer B Oral Oncol 1995;31B:291–298.PubMedCrossRefGoogle Scholar
  167. 167.
    Serrano M, Lee H, Chin L, et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 1996;85:27–37.PubMedCrossRefGoogle Scholar
  168. 168.
    Craig C, Kim M, Ohri E, et al. Effects of adenovirus-mediated p16INK4A expression on cell cycle arrest are determined by endogenous p16 and Rb status in human cancer cells. Oncogene 1998;16:265–272.PubMedCrossRefGoogle Scholar
  169. 169.
    Niculescu AB 3rd, Chen X, Smeets M, et al. Effects of p21(Cip1/Waf1) at both the G1/S and the G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication. Mol Cell Biol 1998;18:629–643.PubMedGoogle Scholar
  170. 170.
    Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999;13:1501–1512.PubMedCrossRefGoogle Scholar
  171. 171.
    Ohtani N, Yamakoshi K, Takahashi A, Hara E. The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression. J Med Invest 2004;51:146–153.PubMedCrossRefGoogle Scholar
  172. 172.
    Chellapan SP. The E2F transcription factor: role in cell cycle regulation and differentiation. Mol Cell Diff 1994;2:201–220.Google Scholar
  173. 173.
    Schwarz JK, Bassing CH, Kovesdi I, et al. Expression of the E2F1 transcription factor overcomes type beta transforming growth factor-mediated growth suppression. Proc Natl Acad Sci USA 1995;92:483–487.PubMedCrossRefGoogle Scholar
  174. 174.
    Hurford RK, Jr., Cobrinik D, Lee MH, Dyson N. pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes. Genes Dev 1997;11:1447–1463.PubMedCrossRefGoogle Scholar
  175. 175.
    Ohtani K. Implication of transcription factor E2F in regulation of DNA replication. Front Biosci 1999;4:D793–D804.PubMedCrossRefGoogle Scholar
  176. 176.
    Humbert PO, Verona R, Trimarchi JM, et al. E2f3 is critical for normal cellular proliferation. Genes Dev 2000;14:690–703.PubMedGoogle Scholar
  177. 177.
    Ren B, Cam H, Takahashi Y, et al. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev 2002, 16:245–256.PubMedCrossRefGoogle Scholar
  178. 178.
    Schlisio S, Halperin T, Vidal M, Nevins JR. Interaction of YY1 with E2Fs, mediated by RYBP, provides a mechanism for specificity of E2F function. EMBO J 2002;21:5775–5786.PubMedCrossRefGoogle Scholar
  179. 179.
    Stevaux O, Dyson NJ. A revised picture of the E2F transcriptional network and RB function. Curr Opin Cell Biol 2002;14:684–691.PubMedCrossRefGoogle Scholar
  180. 180.
    Mundle SD, Saberwal G. Evolving intricacies and implications of E2F-1 regulation. EMBO J 2003;17:569–574.Google Scholar
  181. 181.
    Rogoff HA, Kowalik TF. Life, death and E2F: linking proliferation control and DNA damage signaling via E2F1. Cell Cycle 2004;3:845–846.PubMedGoogle Scholar
  182. 182.
    Korenjak M, Brehm A. E2F-Rb complexes regulating transcription of genes important for differentiation and development. Curr Opin Genet Dev 2005;15:520–527.PubMedCrossRefGoogle Scholar
  183. 183.
    Henriksson M, Luscher B. Proteins of the Myc network: essential regulators of cell growth and differentiation. Adv Cancer Res 1996;68:109–182.PubMedCrossRefGoogle Scholar
  184. 184.
    Schmidt EV. MYC family ties. Nature Genet 1996;14:8–10.PubMedCrossRefGoogle Scholar
  185. 185.
    Amati B, Alevizopoulos K, Vlach J. Myc and the cell cycle. Front Biosci 1998;3:D250–D268.PubMedGoogle Scholar
  186. 186.
    Burgin A, Bouchard C, Eilers M. Control of cell proliferation by Myc proteins. Results Probl Cell Differ 1998;22:181–197.PubMedGoogle Scholar
  187. 187.
    Matsumura I, Tanaka H, Kanakura Y. E2F1 and c-Myc in cell growth and death. Cell Cycle 2003;2:333–338.PubMedGoogle Scholar
  188. 188.
    Yam CH, Fung TK, Poon RY. Cyclin A in cell cycle control and cancer. Cell Mol Life Sci 2002;59:1317–1326.PubMedCrossRefGoogle Scholar
  189. 189.
    Porter LA, Donoghue DJ. Cyclin B1 and CDK1: nuclear localization and upstream regulators. Prog Cell Cycle Res 2003;5:335–347.PubMedGoogle Scholar
  190. 190.
    Livingstone LR, White A, Sprouse J, et al. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 1992;70:923–935.PubMedCrossRefGoogle Scholar
  191. 191.
    Harper JW, Adami GR, Wei N, et al. The p21 cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993;75:805–816.PubMedCrossRefGoogle Scholar
  192. 192.
    Xiong Y, Hannon GJ, Zhang H, et al. p21 is a universal inhibitor of cyclin kinases. Nature 1993;366:701–704.PubMedCrossRefGoogle Scholar
  193. 193.
    Chen CY, Oliner JD, Zhan Q, et al. Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway. Proc Natl Acad Sci USA 1994;91:2684–2688.PubMedCrossRefGoogle Scholar
  194. 194.
    El-Deiry WS, Harper JW, O’Connor PM, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 1994;54:1169–1174.PubMedGoogle Scholar
  195. 195.
    Chen X, Bargonetti J, Prives C. p53, through p21 (WAF1/CIP1), induces cyclin D1 synthesis. Cancer Res 1995;55:4257–4263.PubMedGoogle Scholar
  196. 196.
    Del Sal G, Murphy M, Ruaro E, et al. Cyclin D1 and p21/waf1 are both involved in p53 growth suppression. Oncogene 1996;12:177–185.PubMedGoogle Scholar
  197. 197.
    Laiho M, DeCaprio JA, Ludlow JW, et al. Growth inhibition by TGF-beta linked to suppression of retinoblastoma protein phosphorylation. Cell 1990;62:175–185.PubMedCrossRefGoogle Scholar
  198. 198.
    Ewen ME, Sluss HK, Whitehouse LL, Livingston DM. TGF beta inhibition of Cdk4 synthesis is linked to cell cycle arrest. Cell 1993;74:1009–1020.PubMedCrossRefGoogle Scholar
  199. 199.
    Foulkes WD, Flanders TY, Pollock PM, Hayward NK. The CDKN2A (p16) gene and human cancer. Mol Med 1997;3:5–20.PubMedGoogle Scholar
  200. 200.
    Serrano M. The tumor suppressor protein p16INK4a. Exp Cell Res 1997;237:7–13.PubMedCrossRefGoogle Scholar
  201. 201.
    Carnero A, Hannon GJ. The INK4 family of CDK inhibitors. Curr Top Microbiol Immunol 1998;227:43–55.PubMedGoogle Scholar
  202. 202.
    Huschtscha LI, Reddel RR. p16(INK4a) and the control of cellular proliferative life span. Carcinogenesis 1999;20:921–926.PubMedCrossRefGoogle Scholar
  203. 203.
    Roussel MF. The INK4 family of cell cycle inhibitors in cancer. Oncogene 1999;18:5311–5317.PubMedCrossRefGoogle Scholar
  204. 204.
    Shapiro GI, Edwards CD, Rollins BJ. The physiology of p16(INK4A)-mediated G1 proliferative arrest. Cell Biochem Biophys 2000;33:189–197.PubMedCrossRefGoogle Scholar
  205. 205.
    Chin L, Pomerantz J, DePinho RA. The INK4a/ARF tumor suppressor: one gene-two products-two pathways. Trends Biochem Sci 1998;23:291–296.PubMedCrossRefGoogle Scholar
  206. 206.
    Stott FJ, Bates S, James MC, et al. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J 1998;17:5001–5014.PubMedCrossRefGoogle Scholar
  207. 207.
    James MC, Peters G. Alternative product of the p16/CKDN2A locus connects the Rb and p53 tumor suppressors. Prog Cell Cycle Res 2000;4:71–81.PubMedGoogle Scholar
  208. 208.
    Weber HO, Samuel T, Rauch P, Funk JO. Human p14(ARF)-mediated cell cycle arrest strictly depends on intact p53 signaling pathways. Oncogene 2002;21:3207–12.PubMedCrossRefGoogle Scholar
  209. 209.
    Satyanarayana A, Rudolph KL. p16 and ARF: activation of teenage proteins in old age. J Clin Invest 2004;114:1237–1240.PubMedGoogle Scholar
  210. 210.
    Laval J, Jurado J, Saparbaev M, Sidorkina O. Antimutagenic role of base-excision repair enzymes upon free radical-induced DNA damage. Mutat Res 1998;402:93–102.PubMedGoogle Scholar
  211. 211.
    Boiteux S, Radicella JP. Base excision repair of 8-hydroxyguanine protects DNA from endogenous oxidative stress. Biochimie 1999;81:59–67.PubMedCrossRefGoogle Scholar
  212. 212.
    Boiteux S, Radicella JP. The human OGG1 gene: structure, functions, and its implication in the process of carcinogenesis. Arch Biochem Biophys 2000;377:1–8.PubMedCrossRefGoogle Scholar
  213. 213.
    Nishimura S. Mammalian Ogg1/Mmh gene plays a major role in repair of the 8-hydroxyguanine lesion in DNA. Prog Nucleic Acid Res Mol Biol 2001;68:107–123.PubMedCrossRefGoogle Scholar
  214. 214.
    Nishimura S. Involvement of mammalian OGG1(MMH) in excision of the 8-hydroxyguanine residue in DNA. Free Radic Biol Med 2002;32:813–821.PubMedCrossRefGoogle Scholar
  215. 215.
    Fortini P, Pascucci B, Parlanti E, et al. 8-Oxoguanine DNA damage: at the crossroad of alternative repair pathways. Mutat Res 2003;531:127–139.PubMedGoogle Scholar
  216. 216.
    Nakabeppu Y, Tsuchimoto D, Furuichi M, Sakumi K. The defense mechanisms in mammalian cells against oxidative damage in nucleic acids and their involvement in the suppression of mutagenesis and cell death. Free Radic Res 2004;38:423–429.PubMedCrossRefGoogle Scholar
  217. 217.
    Thompson LH, West MG. XRCC1 keeps DNA from getting stranded. Mutat Res 2000;459:1–18.PubMedGoogle Scholar
  218. 218.
    Tomkinson AE, Chen L, Dong Z, et al. Completion of base excision repair by mammalian DNA ligases. Prog Nucleic Acid Res Mol Biol 2001;68:151–164.PubMedCrossRefGoogle Scholar
  219. 219.
    Caldecott KW. XRCC1 and DNA strand break repair. DNA Repair (Amst) 2003;2:955–969.CrossRefGoogle Scholar
  220. 220.
    Dianov GL, Sleeth KM, Dianova II, Allinson SL. Repair of abasic sites in DNA. Mutat Res 2003;531:157–163.PubMedGoogle Scholar
  221. 221.
    Malanga M, Althaus FR. The role of poly(ADP-ribose) in the DNA damage signaling network. Biochem Cell Biol 2005;83:354–364.PubMedCrossRefGoogle Scholar
  222. 222.
    Williams RS, Bernstein N, Lee MS, et al. Structural basis for phosphorylation-dependent signaling in the DNA-damage response. Biochem Cell Biol 2005;83:721–727.PubMedCrossRefGoogle Scholar
  223. 223.
    Johnson RT, Squires S. The XPD complementation group. Insights into xeroderma pigmentosum, Cockayne’s syndrome and trichothiodystrophy. Mutat Res 1992;273:97–118.PubMedGoogle Scholar
  224. 224.
    Wood RD. DNA damage recognition during nucleotide excision repair in mammalian cells. Biochimie 1999;81:39–44.PubMedCrossRefGoogle Scholar
  225. 225.
    Bernstein C, Bernstein H, Payne CM, Garewal H. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat Res 2002;511:145–178.PubMedCrossRefGoogle Scholar
  226. 226.
    Chen J, Suter B. Xpd, a structural bridge and a functional link. Cell Cycle 2003;2:503–506.PubMedGoogle Scholar
  227. 227.
    MacPhee DG. Mismatch repair as a source of mutations in non-dividing cells. Genetica 1996;97:183–195.PubMedCrossRefGoogle Scholar
  228. 228.
    Peltomaki P. DNA mismatch repair gene mutations in human cancer. Environ Health Perspect 1997;105(Suppl 4):775–780.PubMedCrossRefGoogle Scholar
  229. 229.
    Kirkpatrick DT. Roles of the DNA mismatch repair and nucleotide excision repair proteins during meiosis. Cell Mol Life Sci 1999;55:437–449.PubMedCrossRefGoogle Scholar
  230. 230.
    Kolodner RD, Marsischky GT. Eukaryotic DNA mismatch repair. Curr Opin Genet Dev 1999;9:89–96.PubMedCrossRefGoogle Scholar
  231. 231.
    Harfe BD, Jinks-Robertson S. Mismatch repair proteins and mitotic genome stability. Mutat Res 2000;451:151–167.PubMedGoogle Scholar
  232. 232.
    Harfe BD, Jinks-Robertson S. DNA mismatch repair and genetic instability. Annu Rev Genet 2000;34:359–399.PubMedCrossRefGoogle Scholar
  233. 233.
    Aquilina G, Bignami M. Mismatch repair in correction of replication errors and processing of DNA damage. J Cell Physiol 2001;187:145–154.PubMedCrossRefGoogle Scholar
  234. 234.
    Hsieh P. Molecular mechanisms of DNA mismatch repair. Mutat Res 2001;486:71–87.PubMedGoogle Scholar
  235. 235.
    Schofield MJ, Hsieh P. DNA mismatch repair: molecular mechanisms and biological function. Annu Rev Microbiol 2003;57:579–608.PubMedCrossRefGoogle Scholar
  236. 236.
    Isaacs RJ, Spielmann HP. A model for initial DNA lesion recognition by NER and MMR based on local conformational flexibility. DNA Repair (Amst) 2004;3:455–464.CrossRefGoogle Scholar
  237. 237.
    Stojic L, Brun R, Jiricny J. Mismatch repair and DNA damage signalling. DNA Repair (Amst) 2004;3:1091–1101.CrossRefGoogle Scholar
  238. 238.
    Kunkel TA, Erie DA. DNA mismatch repair. Annu Rev Biochem 2005;74:681–710.PubMedCrossRefGoogle Scholar
  239. 239.
    Jun SH, Kim TG, Ban C. DNA mismatch repair system. Classical and fresh roles. FEBS J 2006;273:1609–1619.PubMedCrossRefGoogle Scholar
  240. 240.
    Montesano R, Becker R, Hall J, et al. Repair of DNA alkylation adducts in mammalian cells. Biochimie 1985;67:919–928.PubMedCrossRefGoogle Scholar
  241. 241.
    D’Incalci M, Citti L, Taverna P, Catapano CV. Importance of the DNA repair enzyme O6-alkyl guanine alkyltransferase (AT) in cancer chemotherapy. Cancer Treat Rev 1988;15:279–292.PubMedCrossRefGoogle Scholar
  242. 242.
    Pegg AE, Byers TL. Repair of DNA containing O6-alkylguanine. FASEB J 1992;6:2302–2310.PubMedGoogle Scholar
  243. 243.
    Sekiguchi M, Nakabeppu Y, Sakumi K, Tuzuki T. DNA-repair methyltransferase as a molecular device for preventing mutation and cancer. J Cancer Res Clin Oncol 1996;122:199–206.PubMedCrossRefGoogle Scholar
  244. 244.
    Pieper RO. Understanding and manipulating O6-methylguanine-DNA methyltransferase expression. Pharmacol Ther 1997;74:285–297.PubMedCrossRefGoogle Scholar
  245. 245.
    Sekiguchi M, Sakumi K. Roles of DNA repair methyltransferase in mutagenesis and carcinogenesis. Jpn J Hum Genet 1997;42:389–399.PubMedCrossRefGoogle Scholar
  246. 246.
    Yu Z, Chen J, Ford BN, et al. Human DNA repair systems: an overview. Environ Mol Mutagen 1999;33:3–20.PubMedCrossRefGoogle Scholar
  247. 247.
    Kaina B, Ochs K, Grosch S, et al. BER, MGMT, and MMR in defense against alkylation-induced genotoxicity and apoptosis. Prog Nucleic Acid Res Mol Biol 2001;68:41–54.PubMedCrossRefGoogle Scholar
  248. 248.
    Drablos F, Feyzi E, Aas PA, et al. Alkylation damage in DNA and RNA—repair mechanisms and medical significance. DNA Repair (Amst) 2004;3:1389–1407.CrossRefGoogle Scholar
  249. 249.
    Gerson SL. MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer 2004;4:296–307.PubMedCrossRefGoogle Scholar
  250. 250.
    Varon R, Vissinga C, Platzer M, et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 1998;93:467–476.PubMedCrossRefGoogle Scholar
  251. 251.
    Buscemi G, Savio C, Zannini L, et al. CHK2 activation dependence on NBS1 after DNA damage. Mol Cell Biol 2001;21:5214–5222.PubMedCrossRefGoogle Scholar
  252. 252.
    Xu B, Kim S, Kastan MB. Involvement of BRCA1 in Sphase and G(2)-phase checkpoints after ionizing irradiation. Mol Cell Biol 2001;21:3445–3450.PubMedCrossRefGoogle Scholar
  253. 253.
    D’Amours D, Jackson SP. The MRE11 complex: At the crossroads of DNA repair and checkpoint signalling. Nat Rev Mol Cell Biol 2002;3:317–327.PubMedCrossRefGoogle Scholar
  254. 254.
    Girard PM, Riballo E, Begg AC, et al. NBS1 promotes ATM dependent phosphorylation events including those required for G1/S arrest. Oncogene 2002;21:4191–4199.PubMedCrossRefGoogle Scholar
  255. 255.
    Huang J, Dynan WS. Reconstitution of the mammalian DNA double-strand break end-joining reaction reveals a requirement for an MRE11/RAD50/NBS1-containing fraction. Nucleic Acids Res 2002;30:667–674.PubMedCrossRefGoogle Scholar
  256. 256.
    Nakanishi K, Taniguchi T, Ranganathan V, et al. Interaction of FANCD2 and NBS1 in the DNA damage response. Nat Cell Biol 2002;4:913–920.PubMedCrossRefGoogle Scholar
  257. 257.
    Osborn AJ, Elledge SJ, Zou L. Checking on the fork: the DNA-replication stress-response pathway. Trends Cell Biol 2002;12:509–516.PubMedCrossRefGoogle Scholar
  258. 258.
    Yazdi PT, Wang Y, Zhao S, et al. SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint. Genes Dev 2002;16:571–582.PubMedCrossRefGoogle Scholar
  259. 259.
    Carson CT, Schwartz RA, Stracker TH, et al. The MRE11 complex is required for ATM activation and the G2/M checkpoint. EMBO J 2003;22:6610–6620.PubMedCrossRefGoogle Scholar
  260. 260.
    Goodarzi AA, Block WD, Lees-Miller SP. The role of ATM and ATR in DNA damage-induced cell cycle control. Prog Cell Cycle Res 2003;5:393–411.PubMedGoogle Scholar
  261. 261.
    Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 2003;3:155–168.PubMedCrossRefGoogle Scholar
  262. 262.
    Uziel T, Lerenthal Y, Moyal L, et al. Requirement of the MRN complex for ATM activation by DNA damage. EMBO J 2003;22:5612–5621.PubMedCrossRefGoogle Scholar
  263. 263.
    Abraham RT. PI 3-kinase related kinases: “big” players in stress-induced signaling pathways. DNA Repair (Amst) 2004;3:883–887.CrossRefGoogle Scholar
  264. 264.
    Lee JH, Paull TT. Direct activation of the ATM protein kinase by the MRE11/RAD50/NBS1 complex. Science 2004;304:93–96.PubMedCrossRefGoogle Scholar
  265. 265.
    Matsuura S, Kobayashi J, Tauchi H, Komatsu K. Nijmegen breakage syndrome and DNA double strand break repair by NBS1 complex. Adv Biophys 2004;38:65–80.CrossRefGoogle Scholar
  266. 266.
    Lavin MF, Birrell G, Chen P, et al. ATM signaling and genomic stability in response to DNA damage. Mutat Res 2005;569:123–132.PubMedGoogle Scholar
  267. 267.
    Lee JH, Paull TT. ATM activation by DNA double-strand breaks through the MRE11-RAD50-NBS1 complex. Science 2005;308:551–554.PubMedCrossRefGoogle Scholar
  268. 268.
    O’Driscoll M, Jeggo PA. The role of double-strand break repair—insights from human genetics. Nat Rev Genet 2006;7:45–54.PubMedCrossRefGoogle Scholar
  269. 269.
    Zhang Y, Zhou J, Lim CU. The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control. Cell Res 2006;16:45–54.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Philip T. Cagle
    • 1
    • 2
  1. 1.Pathology and Laboratory MedicineWeill Medical College of Cornell UniversityNew York
  2. 2.The Methodist HospitalHoustonUSA

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