Cell Cycle Control in Pancreatic Cancer Pathogenesis

  • Brian Lewis
Reference work entry


All multicellular organisms arise from the division of a single cell. Thus, to generate a complex living organism, these cell divisions must be performed with extremely high fidelity and reproducibility during the development of the organism. Furthermore, in the mature, or adult, organism, tissue and organismal homeostasis must be maintained, and this requires the coordination of cell division with cell growth and cell death. These needs have led to the evolution of a cell replication process, known as the cell division cycle, that is highly conserved among all eukaryotes from simple single cellular organisms such as budding yeast to complex mammals such as humans.

Pioneering studies by Lee Hartwell, performed in budding yeast, laid the groundwork for the identification and characterization of the key positive and negative regulators of this process. Given the importance of the regulation of the cell division cycle and its high fidelity execution to organismal homeostasis, it is unsurprising that alteration of the cell cycle is a hallmark feature of human malignancies. Importantly, many of the genes encoding key regulators of the cell cycle are mutated in both sporadic and hereditary forms of cancer including pancreatic cancers.

This chapter will provide an overview of the cell division cycle, as well as describe several of the key regulatory mechanisms that promote its high fidelity. The chapter will then illustrate how the cell cycle is altered in cancer cells, and how this contributes to cancer pathogenesis. Finally, the chapter will focus on pancreatic cancer, with an emphasis on understanding how many of the common genetic alterations identified in this tumor type contribute to dysregulation of the cell division cycle and to the malignant phenotype in this disease.


Cell Cycle Pancreatic Cancer Pancreatic Cancer Cell Sister Chromatid Ataxia Telangiectasia Mutate 
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.



The author thanks Kirsten A. Hubbard for editorial assistance with the chapter, and Sara K. Evans for providing the figures. Work in the author’s lab is supported by grants from the National Institutes of Health.


  1. 1.
    Chung J, et al.: Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 1992;69(7):1227–1236.CrossRefPubMedGoogle Scholar
  2. 2.
    Peng T, Golub TR, Sabatini DM: The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol Cell Biol 2002;22(15):5575–5584.CrossRefPubMedGoogle Scholar
  3. 3.
    Fingar DC, et al.: mtor controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 2004;24(1):200–216.CrossRefPubMedGoogle Scholar
  4. 4.
    Bell SP, Dutta A: DNA replication in eukaryotic cells. Annu Rev Biochem 2002;71:333–374.CrossRefPubMedGoogle Scholar
  5. 5.
    Greider CW, Blackburn EH: Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 1985;43(2 Pt 1):405–413.CrossRefPubMedGoogle Scholar
  6. 6.
    Harley CB, Futcher AB, Greider CW: Telomeres shorten during ageing of human fibroblasts. Nature 1990;345(6274):458–460.CrossRefPubMedGoogle Scholar
  7. 7.
    Stein G, et al.: Regulation of cell cycle stage-specific transcription of histone genes from chromatin by non-histone chromosomal proteins. Nature 1975;257(5529):764–767.CrossRefPubMedGoogle Scholar
  8. 8.
    Wang ZF, et al.: The protein that binds the 3′ end of histone mrna: a novel RNA-binding protein required for histone pre-mrna processing. Genes Dev 1996;10(23):3028–3040.CrossRefPubMedGoogle Scholar
  9. 9.
    Hartwell LH, Culotti J, Reid B: Genetic control of the cell-division cycle in yeast. I. Detection of mutants. Proc Natl Acad Sci USA 1970;66(2):352–359.CrossRefPubMedGoogle Scholar
  10. 10.
    Evans T, et al.: Cyclin: a protein specified by maternal mrna in sea urchin eggs that is destroyed at each cleavage division. Cell 1983;33(2):389–396.CrossRefPubMedGoogle Scholar
  11. 11.
    Nurse P, Thuriaux P, Nasmyth K: Genetic control of the cell division cycle in the fission yeast Schizosaccharomyces pombe. Mol Gen Genet 1976;146(2):167–178.CrossRefPubMedGoogle Scholar
  12. 12.
    Reed SI, Hadwiger JA, Lorincz AT: Protein kinase activity associated with the product of the yeast cell division cycle gene CDC28. Proc Natl Acad Sci USA 1985;82(12):4055–4059.CrossRefPubMedGoogle Scholar
  13. 13.
    Fesquet D, et al.: The MO15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (cdks) through phosphorylation of Thr161 and its homologues. Embo J 1993;12(8):3111–3121.PubMedGoogle Scholar
  14. 14.
    Poon RY, et al.: The cdc2-related protein p40mo15 is the catalytic subunit of a protein kinase that can activate p33cdk2 and p34cdc2. Embo J 1993;12(8):3123–3132.PubMedGoogle Scholar
  15. 15.
    Solomon MJ, Harper JW, Shuttleworth J: CAK, the p34cdc2 activating kinase, contains a protein identical or closely related to p40mo15. Embo J 1993;12(8):3133–3142.PubMedGoogle Scholar
  16. 16.
    Gould KL, Nurse P: Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature 1989;342(6245):39–45.CrossRefPubMedGoogle Scholar
  17. 17.
    Fantes P: Epistatic gene interactions in the control of division in fission yeast. Nature 1979;279(5712):428–430.CrossRefPubMedGoogle Scholar
  18. 18.
    Harper JW, et al.: The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993;75(4):805–816.CrossRefPubMedGoogle Scholar
  19. 19.
    Serrano M, Hannon GJ, Beach D: A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993;366(6456):704–707.CrossRefPubMedGoogle Scholar
  20. 20.
    Xiong Y, et al.: p21 is a universal inhibitor of cyclin kinases. Nature 1993;366(6456):701–704.CrossRefPubMedGoogle Scholar
  21. 21.
    Kovesdi I, Reichel R, Nevins JR: Role of an adenovirus E2 promoter binding factor in E1A-mediated coordinate gene control. Proc Natl Acad Sci USA 1987;84(8):2180–2184.CrossRefPubMedGoogle Scholar
  22. 22.
    Nevins JR: The Rb/E2F pathway and cancer. Hum Mol Genet 2001;10(7):699–703.CrossRefPubMedGoogle Scholar
  23. 23.
    Hayward WS, Neel BG, Astrin SM: Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis. Nature 1981;290(5806):475–480.CrossRefPubMedGoogle Scholar
  24. 24.
    Myc Cancer Gene. Available from:
  25. 25.
    Peters JM: The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 2006;7(9):644–656.CrossRefPubMedGoogle Scholar
  26. 26.
    Yamasaki L, Pagano M: Cell cycle, proteolysis and cancer. Curr Opin Cell Biol 2004;16(6):623–628.CrossRefPubMedGoogle Scholar
  27. 27.
    Elledge SJ: Cell cycle checkpoints: preventing an identity crisis. Science 1996;274(5293):1664–1672.CrossRefPubMedGoogle Scholar
  28. 28.
    el-Deiry WS, et al.: WAF1, a potential mediator of p53 tumor suppression. Cell 1993;75(4):817–825.CrossRefPubMedGoogle Scholar
  29. 29.
    Hoyt MA, Totis L, Roberts BT: S. Cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 1991;66(3):507–517.CrossRefPubMedGoogle Scholar
  30. 30.
    Li R, Murray AW: Feedback control of mitosis in budding yeast. Cell 1991;66(3):519–531.CrossRefPubMedGoogle Scholar
  31. 31.
    Lou Z, Chen J: Mammalian DNA damage response pathway. Adv Exp Med Biol 2005;570:425–455.CrossRefPubMedGoogle Scholar
  32. 32.
    Savitsky K, et al.: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995;268(5218):1749–1753.CrossRefPubMedGoogle Scholar
  33. 33.
    Bell DW, et al.: Heterozygous germ line hchk2 mutations in Li-Fraumeni syndrome. Science 1999;286(5449):2528–2531.CrossRefPubMedGoogle Scholar
  34. 34.
    Malkin D, et al.: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990;250(4985):1233–1238.CrossRefPubMedGoogle Scholar
  35. 35.
    Leach FS, et al.: Mutations of a muts homolog in hereditary nonpolyposis colorectal cancer. Cell 1993;75(6):1215–1225.CrossRefPubMedGoogle Scholar
  36. 36.
    Nicolaides NC, et al.: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 1994;371(6492):75–80.CrossRefPubMedGoogle Scholar
  37. 37.
    Papadopoulos N, et al.: Mutation of a mutl homolog in hereditary colon cancer. Science 1994;263(5153):1625–1629.CrossRefPubMedGoogle Scholar
  38. 38.
    Hanahan D, Weinberg RA: The Hallmarks of Cancer. Cell 2000;100(1):57–70.CrossRefPubMedGoogle Scholar
  39. 39.
    Serrano M, et al.: Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16ink4a. Cell 1997;88(5):593–602.CrossRefPubMedGoogle Scholar
  40. 40.
    Counter CM, et al.: Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. Embo J 1992;11(5):1921–1929.PubMedGoogle Scholar
  41. 41.
    Kim NW, et al.: Specific association of human telomerase activity with immortal cells and cancer. Science 1994;266(5193):2011–2015.CrossRefPubMedGoogle Scholar
  42. 42.
    Rudolph KL, et al.: Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 1999;96(5):701–712.CrossRefPubMedGoogle Scholar
  43. 43.
    Greenberg RA, et al.: Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse. Cell 1999;97(4):515–525.CrossRefPubMedGoogle Scholar
  44. 44.
    Chin L, et al.: p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 1999;97(4):527–538.CrossRefPubMedGoogle Scholar
  45. 45.
    Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285(21):1182–1186.CrossRefPubMedGoogle Scholar
  46. 46.
    Weaver BA, et al.: Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 2007;11(1):25–36.CrossRefPubMedGoogle Scholar
  47. 47.
    Hingorani SR, et al.: Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003;4(6):437–450.CrossRefPubMedGoogle Scholar
  48. 48.
    Aguirre AJ, et al.: High-resolution characterization of the pancreatic adenocarcinoma genome. Proc Natl Acad Sci USA 2004;101(24):9067–9072.CrossRefPubMedGoogle Scholar
  49. 49.
    Jones S, et al.: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321(5897):1801–1806.CrossRefPubMedGoogle Scholar
  50. 50.
    Moskaluk CA, Hruban RH, Kern SE: p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 1997;57(11):2140–2143.PubMedGoogle Scholar
  51. 51.
    Downward J: Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003;3(1):11–22.CrossRefPubMedGoogle Scholar
  52. 52.
    Calhoun ES, et al.: BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. Am J Pathol 2003;163(4):1255–1260.PubMedGoogle Scholar
  53. 53.
    Morton JP, et al.: Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci USA 2007;104(12):5103–5108.CrossRefPubMedGoogle Scholar
  54. 54.
    Kim JW, et al.: Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol 2007;27(21):7381–7393.CrossRefPubMedGoogle Scholar
  55. 55.
    Kamb A, et al.: A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994;264(5157):436–440.CrossRefPubMedGoogle Scholar
  56. 56.
    Kamijo T, et al.: Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19arf. Cell 1997;91(5):649–659.CrossRefPubMedGoogle Scholar
  57. 57.
    Caldas C, et al.: Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 1994;8(1):27–32.CrossRefPubMedGoogle Scholar
  58. 58.
    Zhang Y, Xiong Y, Yarbrough WG: ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1998;92(6):725–734.CrossRefPubMedGoogle Scholar
  59. 59.
    Barton CM, et al.: Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer. Br J Cancer 1991;64(6):1076–1082.PubMedGoogle Scholar
  60. 60.
    Hingorani SR, et al.: Trp53R172H and krasg12d cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005;7(5):469–483.CrossRefPubMedGoogle Scholar
  61. 61.
    Canman CE, et al.: Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 1998;281(5383):1677–1679.CrossRefPubMedGoogle Scholar
  62. 62.
    Hannon GJ, Beach D: p15ink4b is a potential effector of TGF-beta-induced cell cycle arrest. Nature 1994;371(6494):257–261.CrossRefPubMedGoogle Scholar
  63. 63.
    Polyak K, et al.: p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev 1994;8(1):9–22.CrossRefPubMedGoogle Scholar
  64. 64.
    Seoane J, et al.: tgfbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15ink4b. Nat Cell Biol 2001;3(4):400–408.CrossRefPubMedGoogle Scholar
  65. 65.
    Hahn SA, et al.: DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996;271(5247):350–353.CrossRefPubMedGoogle Scholar
  66. 66.
    Lee RC, Feinbaum RL, Ambros V: The C. Elegans heterochronic gene lin-4 encodes small rnas with antisense complementarity to lin-14. Cell 1993;75(5):843–854.CrossRefPubMedGoogle Scholar
  67. 67.
    Bloomston M, et al.: microrna expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. Jama 2007;297(17):1901–1908.CrossRefPubMedGoogle Scholar
  68. 68.
    Calin GA, et al.: A microrna signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005;353(17):1793–1801.CrossRefPubMedGoogle Scholar
  69. 69.
    Volinia S, et al.: A microrna expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 2006;103(7):2257–2261.CrossRefPubMedGoogle Scholar
  70. 70.
    O’Donnell KA, et al.: c-Myc-regulated micrornas modulate E2F1 expression. Nature 2005;435(7043):839–843.CrossRefPubMedGoogle Scholar
  71. 71.
    He L, et al.: A microrna polycistron as a potential human oncogene. Nature 2005;435(7043):828–833.CrossRefPubMedGoogle Scholar
  72. 72.
    Chang TC, et al.: Transactivation of mir-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 2007;26(5):745–752.CrossRefPubMedGoogle Scholar
  73. 73.
    He L, et al.: A microrna component of the p53 tumour suppressor network. Nature 2007;447(7148):1130–1134.CrossRefPubMedGoogle Scholar
  74. 74.
    Yu F, et al.: let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007;131(6):1109–1123.CrossRefPubMedGoogle Scholar
  75. 75.
    Berman DM, et al.: Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003;425(6960):846–851.CrossRefPubMedGoogle Scholar
  76. 76.
    Pasca di Magliano M, et al.: Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev 2006;20(22):3161–3173.CrossRefPubMedGoogle Scholar
  77. 77.
    Thayer SP, et al.: Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003;425(6960):851–856.CrossRefPubMedGoogle Scholar
  78. 78.
    Apte MV, et al.: Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 2004;29(3):179–187.CrossRefPubMedGoogle Scholar
  79. 79.
    Vonlaufen A, et al.: Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res 2008;68(7):2085–2093.CrossRefPubMedGoogle Scholar
  80. 80.
    Shim H, et al.: c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci USA 1997;94(13):6658–6663.CrossRefPubMedGoogle Scholar
  81. 81.
    Shim H, et al.: A unique glucose-dependent apoptotic pathway induced by c-Myc. Proc Natl Acad Sci USA 1998;95(4):1511–1516.CrossRefPubMedGoogle Scholar

Other Resources

  1. Morgan, DO: The Cell Cycle: Principles of Control. London: New Science Press.2007.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Brian Lewis
    • 1
  1. 1.University of Massachusetts Medical SchoolWorcesterUSA

Personalised recommendations