HÜCRE SİKLUSU VE KANSER

Hücre çoğalması ve hücre siklusunun ilerlemesi büyümenin kontrolünde rolü olan genlerin ekspresyonu ilebağlantılıdır. Ökaryot hücre siklusu M (mitoz) G , S ve G fazlarından oluşmaktadır. Bu süreçte hücre uyarımı vebüyüme meydana gelir veya hücre G fazında durmaktadır. Hücre siklusunda G -S geçişinde, G -M geçişinde vemetafaz-anafaz geçişinde kontrol noktaları bulunmaktadır. Hücre siklusu siklin bağımlı kinazlar (cdk, katalitikaltbirim) ve siklin (cyc, düzenleyici altbirim) tarafından kontrol edilmektedir. Hücre homeostazisi hücreçoğalması, büyümenin durdurulması ve apoptozis (programlı hücre ölümü) ile sürdürülmektedir. Hücre siklusuiçindeki olayları düzenleyen ve kontrol eden etkileşimler çok sayıda ve komplekstir. Hücre siklusunundüzenlenmesindeki hatalar hücre bölünmesinin kontrolunun bozulmasına neden olur. Hücre siklusu kontrolnoktalarında değişimler kanser gelişimine neden olabilir. Kanser gelişiminde tümör baskılayıcı fonksiyon, DNAonarımı ve apoptozis kritik yolaklardır

Anahtar Kelimeler:

Hücre siklusu, siklinler, siklin bağımlı kinazlar, tümör baskılayıcı gen, kanser

Cell Cycle and Cancer

Proliferation and cell cycle progression are linked to the expression of genes associated with growth control. The eucaryotic cell cycle consists of an M (mitotic) phase, a G phase, the S phase and G phase. Non-dividing cells exist at G . Cell cycle is regulated by several critical cell cycle check points These are G -S check point, G -M check point and metaphase-anaphase check point. Cell cycle is controlled by the cycline dependent kinases (cdk, catalytic subunit) and cyclins (cyc, regulatory subunit). Homeostasis is within a cell is regulated by the balance between proliferation, growth arrest and apopto sis. Defects in cell cycle regulation inhibit controls for cell division. Alterations of cell cycle check points might result in cancer. The interactions which control and regulate the cascade of events within cell cycle are numerous and complex. Tumor supression of growth arrest, DNA repair and apoptosis, are all critical pathways in the development of cancers.

Keywords:

Cell cycle, cycline, cycline dependent kinases, tümorsupressor gene, cancer,

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1. Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell JE. Molecular Cell Biology. 4 edition:WH Freeman and Co, NewYork, 2000.
2. Vermeulen K, VanBockstaele DR, Berneman Z N. The cell cycle : a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 2003; 36: 131- 49.
3. Guimaras CA, Linden R. Apoptosis and alternative deastyles. Eur J Biochem 2004; 271: 1638-50.
4. ZongWX, Thompson CB. Necrotic death as a cell fate? Genes Dev 2006; 20 : 1-15.
5. Bellamy COC. p53 and apoptosis. Br Med Bull 1996; 53(3): 522-38.
6. DeVita Jr VT, Hellman S, Rosenberg SA. Cancer: principles and practice of oncolgy. 5 edition: Lippincott-Raven, Philadelphia, 1997.
7. Vermeulen K, Berneman ZN, vanBockstaele DR. Cell cycle and apoptosis. Cell Prolif 2003; 36: 165-75.
8. Öndağ Cabadak H. İnsan periferal kan ve fibroblast hücre kültürlerinin sinkronizasyonu ve sinkronize hücre kültürlerinden kromozom analizi ve karyotip hazırlanması. Yüksek Lisans Tezi, Ankara: Gazi Üniversitesi Tıp Fakültesi Tıbbi Biyoloji ve Genetik Anabilim Dalı, 1987.
9. Foster I. Cancer: A cell cycle defect. Radiography 2008; 14: 144-9.
10. Hu W, Feng Z, Teresky AK, Levine AJ. p53 regulates maternal reproduction through LIF. Nature 2007; 450(7170): 721-4.
11. Kearns WG, Liu JM. Cell cycle checkpoint genes and aneuploidy:A short review. Current Genomics 2001; 2: 171-80.
12. Giacinti C, Giordano A. RB and cell cycle progression. Oncogene 2006; 25: 5220-7.
13. Kelly TJ, Brown GW. Regulation of chromosome replication.Annu Rev Biochem 2000; 69: 829-80. |
14. Prasanth SG, Mendez J, Prasanth KV, Stillman B. Dynamics of pre-replication complex proteins during the cell division cycle. Phil Trans R Soc Lond B 2004; 359: 7-16.
15. Flatt PM, Pietenpol JA. Mechanisms of cell-cycle checkpoints: at the cross roads of carcinogenesis and drug discovery. Drug Metab Rev 2000; 32: 283-305.
16. Sears RC,Nevins JR. Signalling networks that link cell proliferation and cell fate. J Biol Chem 2002; 277: 11617-20.
17. Stevaux O, Dyson NJ. A revised picture of the E2F transcriptional network and RB function. Curr Opin Cell Biol 2002; 14: 684-91.
18. Fearson E. Human cancer syndromes: clues to the origin and nature of cancer. Science 1997; 278: 1043- 50.
19. Molinari M. Cell cycle check points and their activation in human cancer. Cell Prolif 2000; 33: 261-74.
20. Cheng M, Sexl V, Sherr C, Raussel M. Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1) Proc NatalAcad Sci 1998; 95: 1091-4.
21. Hartwell LH, Kastan MB. Cell cycle and cancer. Science 1994; 266:1821-8.
22. Kirsch DG, Kastan MB. Tumor-suppressor p53: implications for tumor development and prognosis. J Clin Oncol 1998; 16(9): 3158-68.
23. Dyson NJ. A revised picture of the E2F transcriptional network and RB function. Curr Opin Cell Biol 2002; 14(6): 684-91.
24. Weinberg R. The retinoblastoma protein and cell cycle control. Cell 1995; 81: 323-30.
25. King RJB. Cancer biology, Longman, 1996.
26. Fearson E. Human cancer syndromes: clues to the origin and nature of cancer. Science 1997; 278: 1043- 50.
27. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70.
28. Murray AW. Recycling the cell cycle: cyclins revisited. Cell 2004; 116: 221-34.
29. Hopfner R, Mousli M, Jeltsch JM, Voulgaris A, Lutz Y, Marin C, Bellocq JP, Oudet P, Bronner C. ICBP90, a novel human CCAAT binding protein, involved in the regulation of topoisomerase II expression. Cancer Res 2000; 60: 121-8.
30. Harbour JW, Dean DC. The Rb/E2F pathway: expanding roles and emerging paradigsm. Genes Dev 2000; 14: 2393-409.
31. Zhang HS, Postigo AA, Dean DC. Active transcriptional repression by the Rb-E2F complex mediates G1 arrest triggered by p16INK4a, TGFbeta, and contact inhibition. Cell 1999; 97: 53-61.
32. Hinchcliffe EH, Thompson EA, Maller JL, Sluder G. Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts. Science 1999; 283 (5403): 851-4.
33. Champard JC, Lefloch R, Pouyssegur J, Lenormand P. Erk implication in cell cycle regulation. Biochem BiophysActa 2007: 1773(8): 1299-310.
34. Roberts EC, Shapiro PS, Nahreini TS, et al. Distinct cell cycle timing requirements for extracellular signal regulated kinase and phosphoinositide-3-kinase signalling pathways in somatic cell mitosis. Mol Cell Biol 2002; 22: 7226-41.
35. Harper J, Adami G, Wei N, et al. The p21 Cdkinteracting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993; 75: 805-16.
36. Öndağ H. Effects of excess thymidine and methotraxate on human peripheral blood and fibroblast culture, NATO-ASI The Enzyme Catalysis Process Book, 1998.
37. Pines J, Hunter T. Human cell division: the involvement of cyclins A and B1 and multiple cdc2s. Cold Spring Harb Symp Quant Biol 1991; 56: 449-63.
38. Heald R, McLoughlin M, McKeon F. Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated cdc2 kinase. Cell 1993: 74; 463-74.
39. Strausfeld U, Labbé JC, Fesquet D, et al. Dephosphorylation and activation of a p34cdc2/cyclin B complex in vitro by human CDC25 protein. Nature 1991; 351 (6323): 242-56.
40. Draetta G, Eckstein J. Cdc25 protein phosphatases in cell proliferation. Biochim Biophys Acta 1997: 1332: M53-M63.
41. Marumato T, Hirota T, Morisaki T, et al. Roles of aurora -A kinase in mitotic entry and G2 check point in mammalian cells. Genes Cells 2002; 7: 1173-82.
42. Giono LE, Manfredi JJ. The p53 tumor suppressor participates in multiple cell cycle check points. J Cell Physiol 2006; 209: 13-20.
43. Maddika S, Ande SR, Panigrahi S, Paranjothy T, Weglarczyk K, Zuse A, Eshraghi M, Manda KD, Wiechec E, Los M . Cell survival, cell death and cell cycle pathways are inter connected: Implications for cancer therapy. Drug Resist Updat 2007; 10: 13-29.
44. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B. Mutations of mitotic checkpoint genes in human cancers. Nature 1998; 19: 392: 300-3.
45. Cahill DP, da Costa LT, Carson-Walter EB, Kinzler KW, Vogelstein B, Lengauer C. Characterization of MAD2B and Other Mitotic Spindle Checkpoint Genes. Genomicsm 1999; 58: 181-7.
46. Ouyang B, Meadows J, Fukasawa K. Human Bub1: a putative spindle checkpoint kinase closely linked to cell proliferation. Cell Growth Differ 1998; 9(10): 877- 85 .
47. Sazer S. The Schizosaccharomyces pombe spindle checkpoint protein mad2p blocks anaphase and genetically interacts with the anaphase-promoting complex. Proc NatlAcad Sci 1997; 94(15): 7965-70.
48. Basu J, Bousbaa H, Logarinho E, Williams BC, Sunkel CE, Goldberg ML. Mutations in the essential spindle checkpoint gene bub1 cause chromosome missegregation and fail to block apoptosis in Drosophila. J Cell Biol 1999; 146(1): 13-28.
49. Kitagawa R, Rose AM. Components of the spindleassembly checkpoint are essential in Caenorhabditis elegans. Nat Cell Biol 1999; 1(8): 514-21.
50. Dobles M, Liberal V, Scott ML. Benezra R, Sorger PK. Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell 2000; 101(6): 635-45.
51. Waizenegger IC, Hauf S, Meinke A, Peters JM. Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphase. Cell 2000; 103(3): 399-410.
52. Roberts BT, Farr KA, Hoyt MA. The Saccharomyces cerevisiae checkpoint gene BUB1 encodes a novel protein kinase. Mol Cell Biol 1994; 14(12): 8282-91.
53. Taylor SS, McKeon F. The human homologue of Bub3 is required for kinetochore localization of Bub1 and a Mad3/Bub1-related protein kinase. J Cell Biol 1998; 142(1): 1-11
54. Chipuk JE, Green DR. Dissecting p53-dependent apoptosis. Cell Death Differ 2006; 13: 994-1002.
55. Katsan MB, Bartkova JK. The retinoblastoma protein pathway in cell cycle control and cancer. Exp Cell Res 1997; 237: 1-4.
56. Sherr C, Mccormick F. The Rb and p53 pathways in cancer. Cancer Cell 2002; 2: 103-12.
57. Cabadak H, Aydın B, Kan B. Muscarinic agonist and antagonists changes muscarinic receptor and cyclin D1 expression in K562 cells. EMBO '' Molecular mechanisms of cell cycle control in normal and malignant cCells. Spetses Island-Greece,5-8 October 2007: 53.
58. Reifenberger G, Reifenberger J, Ichimura K, et al. Amplification of multiple genes from chromosomal region 12q13-14 in human malignant gliomas: preliminary mapping of the amplicons shows preferential involvement of CDK4, SAS and MDM2. Cancer Res 1994; 54: 4299-303.
59. Arima Y, Hirota T, Bronner C, et al. Down regulation of nuclear protein ICBP 90 by 53/p21Cip1/WAF1 dependent DNA damage checkpoint signals contributes to cell cycle arrest at G1/S transition. Genes Cells 2004; 9: 131-42.
60. Dang T, Bao S, Wang X. Human Rad 9 is required forthe activation of S-phase check point and the maintenance of chromosomal stability. Genes Cells 2005; 10: 287-95.
61. Wahl GM, Carr AM. The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nature Cell Biol 2001; 3: E277-86.
62. Craig A, Scott M, Burch L, Smith G, Ball K, Hupp T Allosteric effects mediate CHK2 phosphorylation of the p53 transactivation domain. Embo Rep 2003; 4: 787-92.
63. Massagué J. G1 cell-cycle control and cancer. Nature 2004; 432: 298-306
64. Latham K, Baker GL, Musunuru K, et al. Cell cycle control and differentiation: mechanisms of proliferative dysfunction in cancer cells. Cancer Detect Prev 1996; 20: 5.
65. Kaldis P. The cdk-activating kinase (CAK): from yeast to mammals. Cell Mol Life Sci 1999; 55: 284-96.
66. Decuadin D, Geley S, Hirsch T, et al. Bcl-2 and Bcl-Xl antagonize the mitochondria dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents. Cancer Res 1997; 52: 62-7.
67. Story M, Kodym R. Signal transduction during apoptosis; implications for cancer therapy. Front Biosci 1998; 3: d365-75.
68. Dixon S,Soriano BJ, Lush RM, Bomer MM, Figg WD. Apoptosis: its role in the development of malignancies and its potential as a novel therapeutic target. Ann Pharmacother 1997; 31: 76-82.
69. Evan G, Littlewood T. A matter of life and cell death. Science 1998; 281: 1317-21.
70. Jin S, Antinore MJ, Lung FD, Dong X, Zhao H, Fan F, Colchagie AB, Blanck P, Roller PP, Fornace AJ, Jr Zhan Q. The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression. J Biol Chem 2000; 275 (22): 16602-8.
71. Harms-Ringdahl M, Nicotera P, Radford JR. Radiation induced apoptosis. Mutat Res 1996; 366: 171-9.
72. Sattler M, Liang H, Nettesheim D, Meadows RP, et al. Structure of Bcl-xL- Bak peptide complex recognition between regulators of apoptosis. Science 1997; 275: 983-6.
73. Taya Y. Rb kinases and Rb-binding proteins: new points of view. TIBS 1997; 22: 14-7.
74. Smith GC, Divecha N, Lakin ND, Jackson SP. DNAdependent protein kinase and related proteins. Biochem Soc Symp 1999; 64: 91-104.
75. Peterson SE, Stellwagen AE, Diede SJ, Singer MS, Haimberger ZW, Johnson CO, Tzoneva M, Gottschling DE. The function of a stem-loop in telomerase RNA is linked to the DNA repair protein Ku. Nature Genet 2001; 27(1): 64-7.
76. Stellwagen AE, Haimberger ZW, Veatch JR, Gottschling DE. Ku interacts with telomerase RNA to promote telomere addition at native and broken chromosome ends. Genes Dev 2003; 17: 2384-95.
77. Bell DW, Varley JM, Szydlo TE, Kang DH,Wahrer DC, Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ, Fraumeni JF, Birch JM, Li FP, Garber JE, Haber DA. Heterozygous germ line hCHK2 mutations in LiFraumeni syndrome. Science 1999; 286(5449): 2528- 31.
78. Takagaki K, Katsuma S, Kaminishi Y, et al. Role of Chk1 and Chk2 in Ara-C-induced differentiation of human leukemia K562 cells. Genes Cells 2005; 10: 97- 106.
79. Shiloh Y, Kastan M B. ATM: genome stability, neuronal development, and cancer cross paths. Adv Cancer Res 2001; 83: 209-54.
80. Marusyk A, DeGregori J. Building a better model of cancer. Cell Division 2006; 1: 24.
81. Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers. Nature 1997; 386: 623-7.
82. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998; 396: 643- 9.
83. Hanks S, Coleman K, Reid S, Plaja A, Firth H, Fitzpatrick D, Kidd A, Mehes K, Nash R, Robin N, Shannon N, Tolmie J, Swansbury J, IrrthumA, Douglas J, Rahman N. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet 2004; 36: 1159-61.
84. Carmena M, EarnshawWC. The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 2003: 4; 842-54.
85. Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 2004; 4: 927-36.
86. Kanda AH, Kawai H, Suto S, Kitajima S, Sato S, Takata T, Tatsuka M. Aurora-B/AIM-1 kinase activity is involved in Ras-mediated cell transformation. Oncogene 2005: 24; 7266-72.
87. Tatsuka M, Sato S, Kitajima S, et al. Overexpression of Aurora-A potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis. Oncogene 2005; 24 1122-27.
88. Pihan GA, Purohit A, Wallace J, Knecht H, Woda B, Quesenberry P, Doxsey SJ. Centrosome defects and genetic instability in malignant tumors. Cancer Res 1998: 58; 3974-85.
89. Yang J, Ikezoe T, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y, Komatsu N, Bandobashi K, Togitani K, Koeffler HP, Taguchi H, Yokoyama A. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest. Blood 2007; 110: 2034-40.
90. Golias C, CharalabopoulosA, Charalabopoulos K. Cell proliferation and cell cycle control: a mini review. Int J Clin Pract 2004; 58: 1134-41.
91. Hattori H, Kuroda M, Ishida T, Shinmura K, Nagal S, Mukal K, et al. Human DNA damage check points and their relevance to soft tissue sarcoma. Pathol Int 2004; 54: 26-31.
92. Blegen H, Einhorn N, Sjovall K, Roschke A, Ghadimi B, McShane L, et al. Prognostic significance of cell cycle proteins and genomic instability in borderline, early and advanced stage ovarian carcinomas. Int J Gynecol Cancer 2000; 10: 477-87.
93. Tse AN,Carvajal R,Schwartz GK. Targeting checkpoint kinase 1 in cancer thera-peutics. Clin Cancer Res 2007; 13(7): 1955-9.
94. Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature 2004; 432: 316-23