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МЕТИЛИРОВАНИЕ ДНК - УНИВЕРСАЛЬНЫЙ МЕХАНИЗМ РЕГУЛЯЦИИ АКТИВНОСТИ ГЕНОВ.

Пендина А.А.

Научно-исследовательский институт акушерства, гинекологии и репродуктологии им. Д.О. Отта, Санкт-Петербург, РФ

Гринкевич В.В.

Санкт-Петербургский государственный университет, Санкт-Петербург, РФ

Кузнецова Т.В.

Научно-исследовательский институт акушерства, гинекологии и репродуктологии им. Д.О. Отта, Санкт-Петербург, РФ

Баранов В.С.

Научно-исследовательский институт акушерства, гинекологии и репродуктологии им. Д.О. Отта, Санкт-Петербург, РФ

Ключевые слова
метилирование ДНК, 5-МЕТИЛЦИТОЗИН, МЕТИЛАЗА, ИМПРИНТИНГ, ОНКОГЕНЕЗ,

Резюме

Метилирование ДНК - один из основных механизмов эпигенетической наследственности эука-риот. В обзоре кратко рассмотрены пути метилирования цитозина, распределение 5-метилцитозина в геноме, механизм инактивации генов, опосредованный гиперметилированием, роль метилирования в геномном импринтинге, при инактивации X хромосомы, в эмбриогенезе млекопитающих, а также в процессах канцерогенеза и в этиологии некоторых распространенных наследственных заболеваний человека

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Ссылки

  1. Баранов В. С. Хромосомный импринтинг и хромосомные взаимодействия в раннем развитии млекопитающих//Успехи современной биологии. -1988. -Т. 105, № 3. -С. 393^105.

  2. Баранов В. С. Хромосомный импринтинг и наследственные болезни//Биополимеры и клетка. -1991. -Т. 7. -С.73-79.

  3. Гинтер Е.К. Медицинская генетика. -М.: Медицина, 2003. -447с.

  4. Залетаев Д.В., Немцова М.В., Бочков Н.П. II Метилирование ДНК как этиологический фактор канцерогенеза//Вестник РАМН. -2002.™№4, -С. 6-11.

  5. Козлова С.И., Дашкова Н.С., Селшнова Е., Блинникова О.Е. Наследственные синдромы и медико-генетическое консультирование. -М.: Практика, 1996. -410 с.

  6. Назаренко С.А. Нарушение эпигенетической регуляции активности генов и болезней человека//Всстн. РАМН. -2001. -№ 10. -С. 43^8.

  7. Немцова М.В. Геномный импринтинг и наследственная патология//Молекулярная биология. -2000. -Т. 34, № 4. -С. 554-560.

  8. Немцова М.В. Нарушения эпигенетической регуляции экспрессии генов как новый класс молекулярной патологии. Автореф.... канд. биол. наук//М., 2002. -48 с.

  9. Amir R.E., Van der Veyver IB., Wan M. et al. Rett syndrome is caused by mutations in X-linkcd MECP2, encoding mcthyl-CpG-binding protein 2//Nat Genet. -1999. -Vol. 23. -P. 185-188.

  10. Antequera E, Bird A. CpG islands//EXS. -1993. -Vol. 64. -P. 169.

  11. Antequera E, Bird A. Number of CpG islands and genes in human and mouse//Proc Natl Acad Sci USA. -1993. -Vol. 90. -P. 11995.

  12. Belinsky S.A., Nikula K.J., Palmisano W.A. et al. Aberrant mcthylation of p 16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis//Proc Natl Acad Sci USA. -1998. -Vol. 95, N20, -P. 11891-11896.

  13. Bestor Т., Laudano A., Mattaliano R., Ingram V. Cloning and sequencing of a cDNA encoding DNA mcthyltransfcrasc of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction mcthyltrasfcrascs//J. Mol. Biol.-1988. -Vol. 203, -P. 971.

  14. Bestor Т.Н. The host defence function of genomic mcthylation patterns//Novartis Found Symp. -1998. -Vol. 214. -P. 187-95, discussion 195-199.

  15. BhatiaK., Siraj A. K., HussainA. et al. The tumor suppressor gene 14-3-3{sigma} is commonly methylated in normal and malignant lymphoid cells//Cancer Epidemiol. Biomarkcrs Prcv. -2003. -Vol. 12, N 2.-P. 165-169.

  16. Bianco Т., Chenevix-Trench G, Walsh D.C. et al. Tumour-specific distribution of BRCA1 promoter region mcthylation supports a pathogenetic role in breast and ovarian cancer//Carcinogenesis. -2000. -Vol. 21, N2, -P. 147-151.

  17. Bird A. The essentials of DNA mcthylation//Cell, -1992. -Vol. 70 -P. 5-8

  18. Bird A.P., Wolffe A.P. Mcthylation-induccd repression -belts, braces, and chromatin//Cell. -1999. -Vol. 99. -P. 451^54.

  19. Bird A.P. Gene number, noise reduction and biological complexity//Trends Genet. -1995. -Vol. 11, N 3. -P. 94-100.

  20. Brandeis M., Kafri T, Ariel M., et al. The ontogeny of allclc-spccific mcthylation associated with imprinted genes in the mouse//EMBO J. -1993. -Vol. 12. -P. 3669-3677.

  21. Chaillet J.R., Vogt Т.Е., Beier D.R. and Leder P. Parental-specific mcthylation of an imprinted transgene is established during gamcto-gencsis and progressively changes during cmbryogencsis//Cell. -1991. -Vol. 66. -P. 77-83.

  22. Consortium Ihgs. Initial sequencing and analysis of the human genome//Nature. -2001. -Vol. 860. -P. 860-921.

  23. Constancia M, Pickard B, Kelsey G, Reik W. Imprinting mechanisms//Genome Res. -1998. -Vol. 8. -P. 881-900.

  24. Costa M, Yan Y, Zhao D, Salnikow K. Molecular mechanisms of nickel carcinogenesis: gene silencing by nickel delivery to the nucleus and gene activation/inactivation by nickel-induced cell signaling//J. Environ Monit. -2003. -Vol. 5, N 2. -P. 222-223.

  25. Deng G.R., Chen A.D., Hong J. et al. Mcthylation of CpG in a small region of the hMLHl promoter invariably correlates with the absence of gene expression//Cancer Res. -1999. -Vol. 59. -P. 2029-2033.

  26. Ehrlich M. DNA mcthylation: normal development, inhcreired diseases and cancer//J. Clin Ligand Assay. -2000. -Vol. 23. -P. 144-146.

  27. Esteller M., Corn PC, Urena J.M., et al. Inactivation of glutathione S-transfcrasc P1 gene by promoter hypcrmethylation in human neoplasia//Cancer Res. -1998. -Vol. 58, N 20. -Vol. 4515^1518.

  28. Esteller M., Garcia-Eoncillas J., Andion E. et al. Inactivation of the DNA-rcpair gene MGMT and the clinical response of gliomas to alkylating agents//N. Engl. 3. Med. -2000. -Vol. 343, N 19. -P. 1350-1354.

  29. Eversole-Cire P., Ferguson-Smith A.C., Sasaki H. et al. Activation of an imprinted Igf2 gene in mouse somatic cell cultures//Mol. Cell. Biol. -1993. -Vol. 13. -P. 4928-4938.

  30. Feinberg A.P, Vogehtein B. Hypomcthylation distinguishes genes of some human cancers from their normal counterparts//Nature. -1983. -Vol. 301, N 5895. -P. 89-92.

  31. Fleisher A.S., Esteller M., Wang S. etal. Hypcrmethylation of the hMLH 1 gene promoter in human gastric cancers with microsatellite instability//Cancer Res. -1999. -Vol. 59. -P. 1090-1095.

  32. Florl A.R., Lower R., Schmitz-Drager B.J. et al. DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas//Br J. Cancer. -1999. -Vol. 80. -№ 9. -P. 1312-1321.

  33. Gama-Sosa M.A., Slagel V.A., Trewyn R.W. et al. The 5-mcthylcytosinc content of DNA from human tumors//Nucleic Acids Res. -1983. -Vol. 11,N 19. -P. 6883-6894.

  34. Goto Т., Monk М. Regulation of X-chromosomc inactivation in development in mice and humans//Microbiology and Molecular Biology Reviews. -1998. -Vol. 62, N 2. -P. 362-378.

  35. Graff J.R, Gabrielson E., Fujii H. et al. Mcthylation patterns of the E-cadhcrin 5' CpG island arc unstable and reflect the dynamic, heterogeneous loss of E-cadhcrin expression during metastatic progression//J. Biol Chcm. -2000. -Vol. 275, N 4. -P. 2727-2732.

  36. Greenblatt M.S., Bennett W.P., llolhtein M., Harris C.C. Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis//Cancer Res. ■-1994. -Vol. 54, N 18. -P. 4855-4878

  37. Greger V, Debus N., Lohmann D., et al. Frequency and parental origin of hypcrmcthylatcd RBI alleles in retinoblastoma//Hum Genet. -1994. -Vol. 94, N 5. -P. 491-496.

  38. Hanaila M., Delia D., Aiellu A. et al. bcl-2 gene hypomcthylation and high-level expression in B-ccll chronic lymphocytic leukemia//Blood. -1993. -Vol. 82, N 6. -P. 1820-1828.

  39. Hendrich В., Bird A. Identification and characterization of a family of mammalian methyl-CpG-binding proteins//Mol Cell Biol. -1998. -Vol. 18.-P. 6538-6547.

  40. Hendrich В., Bird A. Mammalian mcthyltransfcrascs and mcthyl-CpG-binding domains: proteins involved in DNA mcthylation//Curr Top Microbiol Immunol. -2000. -Vol. 249. -P. 55-74.

  41. Herman J. G, Civin С.1., Issa J.P. et al. Distinct patterns of inactivation of pl5INK4B and pI6INK4A characterize the major types of hematological malignancies//Cancer Res. -1997. -Vol. 57, N 5. -P. 837-841.

  42. Herman J.G., Latij F, Weng Y. el al. Silencing of the VHL tumor-suppressor gene by DNA mcthylation in renal carcinoma//Proc Natl Acad Sci USA. -1994. -Vol. 91. -P. 9700-9704.

  43. Hollstein M., Shomer В., Greenblatt M. et al. Somatic point mutations in the p53 gene of human tumors and cell lines: updated compilation//Nucleic Acids Res. -1996. -Vol. 24, N 1. -P. 141-146

  44. ltano O., Veda M., Kikuchi K. et al. A new predictive factor for hepatocellular carcinoma based on two-dimensional electrophoresis of genomic DNA//Oncogene. -2000. -Vol. 19,N 13. -P. 1676-1683.

  45. Jarrard D.F., Bova G.S., Ewing CM. et al. Dclctional, mutational, and mcthylation analyses of CDKN2 (pl6/MTSl) in primary and metastatic prostate cancer//Genes Chrom Cancer. -1997. -Vol. 19, N 2. -P. 90-96.

  46. Jones P.A., Wolkowicz M.J., Rideout W.Md. etal. De novo mcthylation of the MyoDl CpG island during the establishment of immortal cell lines//Proc Natl Acad Sci USA. -1990. -Vol. 87. -P. 6117-6121.

  47. Kafri Т., Ariel M., Brandeis M. et al. Developmental pattern of genc-spccific DNA mcthylation in the mouse embryo and germ line//Genes & Dcv. -1992. -Vol. 6. -P. 705-714.

  48. Kantharidis P., Elosta A., deSilva M. et al. Altered mcthylation of the human MDR1 promoter is associated with acquired multidrug resistance//Clin Cancer Res. -1997. -Vol. 311. -P. 2025-2032.

  49. Katz F, Webb D., Gibbons B. et al. Possible evidence for genomic imprinting in childhood acute mycloblastic leukaemia associated with monosomy for chromosome 7//Br J. Haematol. -1992.-Vol. 80, № 3. -P. 332-336.

  50. Katzenellenbogen R.A., Baylin S.B., Herman J. G. Hypcrmethylation of the DAP-kinasc CpG island is a common alteration in B-ccll malignancies//Blood. -1999. -Vol. 93, N 12. -P. 4347-4353.

  51. Kautiainen T.L., Jones PA. DNA mcthyltransfcrasc levels in tumorigenic and nontumorigenic cells in culture//J. Biol. Chcm. -1986. -Vol. 261, N4. -P. 1594-1598.

  52. Kawakami K., Brabender J., Lord R. V. et al. Hypcrmcthylatcd APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma//J. Natl. Cancer Inst. -2000. -Vol. 92, N 22. -P. 1805-1811.

  53. Knudson A.G. mutation and cancer: statistical study of retinoblastoma. Proc. Nat. Acad. Sci. USA. -1971. -Vol. 68. -P. 820-823.

  54. Kondo M., Matsuoka S., Vchida K. et al. Selective matcrnal-allclc loss in human lung cancers of the maternally expressed p57KIP2 gene at llpl5.5//Oncogene.-1996. -Vol. 12, N6.-P. 1365-1368.

  55. Laird P. W., Jaenisch R. The role of DNA mcthylation in cancer genetic and cpigcnctics//Annu Rev Genet. -1996. -N 30. -P. 441^164.

  56. Lei H., OhS.P, Okano M. etal. Dc novo DNA cytosinc mcthyltransfcrasc activities in mouse embryonic stem cells//Development. -1996. -Vol. 122. -P. 3195.

  57. Lerchner W. and Barlow D.P (1997) Paternal repression of the imprinted mouse Igf2r locus occurs during implantation and is stable in all tissues of the post implantation mouse embryo//Mcch. Dcv. -Vol. 61. -P. 141-149.

  58. Li E., Bestor Т.Н., Jaenisch R. Targeted mutation of the DNA mcthyltransfcrasc gene results in embryonic lethality//Cell. -1992. -Vol. 69.-P. 915.

  59. Malik K., Salpekar A., Hancock A. et al. Identification of differential mcthylation of the WT1 antisense regulatory region and relaxation of imprinting in Wilms' tumor//Cancer Res. -2000. -Vol. 60. -P. 2356-2360.

  60. Miki Y., Nishisho I., Horii A. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer.//Can Res. -1992.-Vol. 52, N 3. -P. 643-645.

  61. Monk M., Boubelik M., Lehnert S. Temporal and regional changes in DNA mcthylation in the embryonic, cxtracmbrionic and germ cell lineages during mouse embryo development//Development.-1987. -Vol. 99.-P. 371-382.

  62. Nan X, Campoy F.J., Bird A. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin//Cell. -1997. -Vol. 88.-P. 471.

  63. Nan X., Cross S., Bird A. Gene silencing by methyl-CpG-binding proteins//Novartis Found Symp. -1998. -Vol. 214. -P. 6-16, discussion 16-21. -P. 46-50.

  64. Narayan A., Ji W., Zhang XY et al. Hypomcthylation of periccntromcric DNA in breast adenocarcinomas//Int J Cancer.-1998.-Vol. 77, N 6. -P. 833-838.

  65. Nass S.J., Herman J.G., Gabrielson E. et al. Aberrant mcthylation of the estrogen receptor and E-cadhcrin 5' CpG islands increases with malignant progression in human breast cancer//Cancer Res. -2000. -Vol. 60. -P. 4346-4348.

  66. Newell-Price J., Adrian J.L., King C, King P. DNA mcthylation and silencing of gene expression//ТЕМ. -2000. -Vol. 11, N 4. -P. 142-148.

  67. Ng H.H., Zhang Y, Hendrich В., Johnson C.A. et al. MBD2 is a transcriptional repressor, belonging to the McCPl histonc dcacctylasc complex//Nat Genet. -1999. -Vol. 23. -P. 58-61.

  68. Nguyen T.T., Mohrbacher A.F., Tsai Y.C, GroffenJ., Heisterkamp N. Nichols P.W., Yu M.C, Lubbert M., Jones PA. Quantitative measure of c-abl and pi5 mcthylation in chronic myelogenous leukemia: biological implications//Blood. -2000. -Vol. 95, N 9. -P. 2990-2992.

  69. Nitovo G.J, Plaia T.W., Belinsky S.A. et al. In situ detection of the hypcrmcthylation-induccd inactivation of the pl6 gene as an early event in oncogenesis//Proc Natl Acad Sci USA. -1999. -Vol. 96, N 22. -P. 12754-12759.

  70. O'Neill R.J.W., Oneill M.J., Graves J.A.M. Undcrmcthylation associated with retroclcmcnt activation and chromosome remodelling in an interspecific mammalian hybrid//Nature. -1998. -Vol. 393. -P. 68-72.

  71. Ogawa O., Eccles M.R., Szeto J. et al. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour//Nature. -1993.-Vol. 362, N 6422. -P. 749-751.

  72. Okano M., Bell D.W., Haber D.A., Li E. DNA mcthyltransfcrascs Dnmt3a and Dnmt3b arc essential for dc novo mcthylation and mammalian development//Cell. -1999. -Vol. 99. -P. 247-257.

  73. Okano M., Xie S., Li E. Dnmt2 is not required for dc novo and maintenance mcthylation of viral DNA in embryonic stem cells//Nucleic Acids Res. -1998. -Vol. 26. -P. 2536.

  74. Palmisano W.A., Divine K.K., Saccomanno G et al. Predicting lung cancer by detecting aberrant promoter mcthylation in sputum//Cancer Res. -2000. -Vol. 60. -P. 5954-5958.

  75. Pfeifer G.P., Denissenko M.F. Formation and repair of DNA lesions in the p53 gene: relation to cancer mutations//Environ Mol Mutagen. -1998.-Vol. 31, N3. -P. 197-205.

  76. Pulford D.J., Falls J. G., Killian J.K., Jirtle R.L. Polymorphisms, genomic imprinting and cancer susceptibility//Mutat Res. -1999. -Vol. 436. -№ 1. -P. 59-67.

  77. Qu G.Z., Dubeau L., Narayan A. et al. Satellite DNA hypomethylation vs overall genomic hypomethylation in ovarian epithelial tumors of different malignant potential//Mutat Res Fund Mol Mech Mutagens. -1999.-Vol. 423, N 1-2, -P. 91-101.

  78. Rainer S., Johnson L.A., Dobry C.J. et al. Relaxation of imprinted genes in human cancer//Nature. -1993. -Vol. 362, N 6422. -P. 747-749.

  79. Ramsahoye B.H., Biniszkiewicz D., Lyko F. et al. Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA mcthyltransferase 3a//Proc Natl Acad Sci USA. -2000. -Vol. 97. -P. 5237-5242.

  80. Razin A. and Shemer R. DNA methylation in early development//Hum. Mol. Genet. -1995. -Vol. 4. -P. 1751-1755.

  81. Razin A. CpG methylation, chromatin structure and gene silencing -a three-way connection//The EMBO Journal. -1998. -Vol. 17, N 17. -P. 4905-4908.

  82. Razin A., Cegar H. DNA methylation and gene expression//Microbiol Rev. -1991. -Vol. 55. -P. 451^158.

  83. RazinA, Kafri T. DNA methylation from cmbrio to adult//Prog. Nucleic. Acid. Res. Mol. Biol. -1994. -Vol. 48. -P. 53-81.

  84. Roman-Gomez J., Castillejo J. A., Jimenez A. et al. 5' CpG island hyper-methylation is associated with transcriptional silencing of the p21CIPl/WAF1/SDI1 gene and confers poor prognosis in acute lymphoblastic leukemia//Blood. -2002. -Vol. 99, N 7. -P. 2291-2296.

  85. Salem C.E., Markl I.D.C., Bender CM. et al. PAX6 methylation and ectopic expression in human tumor cells//Int. J. Cancer. -2000. -Vol. 87, -P. 179-185.

  86. Sanford J.P, Clark H.J., Chapman V.M. and Rossant J. Differences in DNA methylation during oogenesis and spermatogenesis and their persistence during early embryogenesis in the mouse//Genes & Dev. -1987. -Vol. 1. -P. 1039-1046.

  87. Sassaman D.M., Dombroski B.A., Moran J.V. et al. Many human LI elements arc capable of rctrotransposition//Nat Genet. -1997. -Vol. 16,N 1. -P. 37-43.

  88. Simpson D.J., Hibberts N.A., McNicolA.M. et al. Loss ofpRb expression in pituitary adenomas is associated with methylation of the RB1 CpG island//Cancer Res. -2000. -Vol. 60. -P. 1211-1216.

  89. Singal R., Ginder G.D. DNA Methylation//Blood. -1999. -Vol. 93, N 12. -P. 4059^070.

  90. Singer M.F, Krek V, McMillan J.P. et al. Linc-1 -a human transposable element//Gene.-1993. -Vol. 135.N 1-2. -P. 183-188.

  91. Soares J., Pinto A.E., Cunha C.V. Global DNA hypomethylation in breast carcinoma -correlation with prognostic factors and tumor progression//Cancer. -1999. -Vol. 85, N 1. -P. 112-118.

  92. Tada M., Tada Т., Lefebvre L. et al. Embryonic germ cells induce epigenctic rcprogramming of somatic nucleus in hybrid cells//EMBO J. -1997. -Vol. 16. -P. 6510-6520.

  93. Tada Т., Tada M., Hilton K., Barton S.C et al. Epigenotype switching of implantable loci in embryonic germ cells//Dev. Genes Evol. -1998.

  94. Takiguchi M., Achanzar W.E., Qu W, Li G, Waalkes M.P. Effects of cadmium on DNA-(Cytosine-5) mcthyltransferase activity and DNA methylation status during cadmium-induced cellular transformation//Exp Cell Res. -2003. -Vol. 286, N 2. -P. 355-365.

  95. Tate P., Skarnes W, Bird A. The mcthyl-CpG-binding protein McCP2 is essential development in the mouse//Nat Genet. -1996. -Vol. 12. -P. 205.

  96. Tate P.H., Bird A.P. Effects of DNA methylation on DNA-binding proteins and gene expression//Curr Opin Genet Dev. -1993. -Vol. 3. -P. 226.

  97. TaziJ., Bird A. Alternative chromatin structure ofCpG islands//Cell. -1990. -Vol. 60. -P. 909.

  98. Teitz Т., Wei T, Valentine M.B., Vanin E.F., Grenet J., Valentine V.A., Behm F.G., Look A.T, Lahti J.M., Kidd VJ. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN//Nat Med. -2000. -Vol. 6, N 5. -P. 529-535.

  99. Tycko B. Epigenctic gene silencing in cancer//J Clin Invest. -2000, N 105. -P. 401-407.

  100. Tycko B. Genomic imprinting in Wilms' tumor//Med Ped Oncol.-1996.

  101. Venter J. C, Adams M.D., Myers E. W. The sequence of the human geno me//Science. -2001. -Vol. 291. -P. 1304-1350.

  102. Wilson G. N., HallJ.G., de la CruzFII Genomic imprinting: summary of an NICHD Conference//Am. J. Med. Genet. -1993. -Vol. 46. -P. 675-680.

  103. Worm J, Bartkova J., Kirkin A.F., Straten P.T. et al. Aberrant p27(Kipl) promoter methylation in malignant melanoma//Oncogene. -2000. -Vol. 19, N44. -P. 5111-5115.

  104. Wutz A. et al. Imprinted expression of the Igf2r gene depends on an intronic CpG island//Nature. -1997. -Vol. 389. -P. 745-749.

  105. Xu G.L., Bestor Т.Н., Bourc'his D. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA mcthyltransferase gene//Nature. -1999.-Vol. 402. -P. 187-191.

  106. Yanagisawa Y, Akiyama Y, lida S. et al. Methylation of the hMLHl promoter in familial gastric cancer with microsatcllitc instability//Int J. Cancer. -2000. -Vol. 85, N 1. -P. 50-53.

  107. Yen R.W., Vertino P.M., Nelkin B.D. et al. Isolation and characterization of the cDNA encoding human DNA mcthyltransferase//Nucleic Acids Res. -1992. -Vol. 20. -P. 2287.

  108. Zheng S. C, Chen P. C, McMillan A. et al. Correlations of partial and extensi ve methylation at the pl4(ARF) locus with reduced mRNA expression in colorectal cancer cell lines and clinicopathological features in primary tumors//Carcinogenesis. -2000. -Vol. 21, N 11. -P. 2057-2064.

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