Автореферат и диссертация по медицине (14.00.14) на тему:Вирусные и клеточные гены, вовлеченные в HPV-ассоциированный канцерогенез шейки матки
- Ученая степень
- кандидата биологических наук
- ВАК РФ
- 14.00.14
Оглавление диссертации Грицко, Татьяна Михайловна :: 2000 :: Москва
Список основных сокращений
Введение
Глава I. Обзор литературы
Вирусные и генетические аспекты патогенеза рака шейки матки
1.1. Вирусы папиллом человека как этиологический фактор при раке шейки матки
1.1.1.Структура генома HPV и функции вирусных генов
1.1.2.Роль вирусной интеграции
1.1.3. Трансформация клеток под действием вирусов папиллом
1.2. Генетические изменения в опухолевых клетках шейки матки
1.2.1. Подходы к выявлению генов, ассоциированных с канцерогенезом
1.2.2.Ген с-MYВ
1.2.3. Ген SOD
1.2.4. Ген RAR/
Введение диссертации по теме "Онкология", Грицко, Татьяна Михайловна, автореферат
IL 1.Выявление генома HPV типов 16 и 18 в образцах зпухолей и прилегаь;:и.их норл-тт;; лтлллк 41.1.1. PCR с унивеи • ^ j
III.1.2. PCR с типоспецифическими праймерами
II.2. Определение форм персистенцш вирусного генома к л экспрессии эписомальной и интегративной форм HPV тип 16
II.3. Изучение экспрессии клеточных последовательностей î сайтах интеграции HPV тип 16
III.4. Исследование экспрессии гена RARß в опухолевых и прилегающих нормальных тканях шейки матки
II.5. Анализ полиморфизма длины рестрикционных фрагментов генов, локализованных на хромосоме 6 в шухолевых и прилегающих нормальных тканях шейки матки плава IV. Обсуждение результатов выводы ние эо
61 лагодарности
Введение
По эпидемиологическим данным рак шейки матки встречается у 5-48 женщин из 100 ООО. Самый низкий и самый высокий уровень заболеваемости наблюдаются в Испании и Колумбии соответственно [Muir et al.,1987;Ponten et al., 1995]. Этиологическим фактором рака шейки матки признан вирус папиллом человека высокого риска -HPV[WHO Press Release,1996]. Несмотря на активные исследования в этой области онкологии, многие аспекты участия вирусного генома в канцерогенезе остаются неясными. Так, не решен вопрос о роли вирусной интеграции.
Рак шейки матки после вирусной инфекции может развиваться через стадии легкой, умеренной, выраженной интраэпителиалы-гай дисплазии и рака in situ и длиться несколько лет [Kiviat et al., 1992]. Это свидетельствует о том, что кроме присутствия вирусного генетического материала необходимы дополнительные факторы для развития рака. Свой вклад в этот процесс могут вносить клеточные гены, продукты которых влияют на экспрессию как вирусного генома, так и клеточных генов - регуляторов пролиферации. i
Т.о., важной задачей остается исследование структуры и экспрессии клеточных генов, участвующих в процессах канцерогенеза . Целью настоящей работы было изучение интеграции вирусного генома и исследование изменений в экспрессии и структуре нескольких клеточных генов, потенциально вовлеченных в канцерогенез рака шейки матки. Для этого были поставлены следующие задачи:
1). создать банк образцов опухолей шейки матки;
2). провести анализ образцов на наличие вирусов папиллом высокого риска;
3). исследовать форму персистенции вирусной ДНК в клет.те"
4). изучить интеграцию вирусного генома и ее влияние на клеточные последовательности в сайтах интеграции;
5). изучить экспрессию и структуру некоторых клеточных генов, которые потенциально могут быть вовлечены в канцерогенез шейки матки.
В результате исследования и в опухолевых и в прилегающих нормальных тканях шейки матки были выявлены последовательности HPV тип 16 и/или 18. Вирусная ДНК в опухолевых тканях персистировала как в эписомальной, так и в интегративной формах. Интеграция HPV тип 16 происходила неспецифично, в разные участки клеточного генома. Нами впервые показано, что в некоторых опухолях интегрированная вирусная ДНК не экспрессировалась. При исследовании клеточных последовательностей в сайтах интеграции оказалось, что они являются транскрипционно активными как в опухолевых, так и в нормальных тканях шейки матки. В двух опухолях HPV тип 16 интегрировал в последовательности, оказавшиеся гомологичными эндогенному ретровирусу HHERV-1, который индуцируется ретиноевой кислотой (RA). Известно, что действие ретиноевой кислоты опосредовано через рецепторы ретиноевой кислоты - RARs. Показав, что одна из этих клеточных последовательностей экспрессируется в опухолевых тканях шейки матки, мы предположили, что, возможно, активация транскрипции этой последовательности происходит за счет повышенного уровня экспрессии RARs. Для исследования мы выбрали рецептор субтипа ß -RARß, т. к. по литературным данным этот ген является предполагаемым опухолевым супрессором и изменения в его экспрессии ассоциированы со многими типами неоплазий. Для анализа роли других клеточных генов в HPV-ассоциированном канцерогенезе шейки матки исследовали структуру нес коль хих генетических локусов на длинном плече 6 хромосомы - протоонкогена c-MYB, гена супероксиддисмутазы SOD2 , а также минисателлитного локуса D6S37, локализованного в зоне нестабильности в прителомерном районе.
Т.о., проведенное исследование позволило расширить наши знания о роли интеграции HPV в клетках шейки матки и об изменениях в клеточных генах, ассоциированных с канцерогенезом у человека.
Список использованной литературы по медицине, диссертация 2000 года, Грицко, Татьяна Михайловна
1. Ambros P.F.,Karlic H.1.,Chromosomal incertion sites of human papillomaviruses DNA in three cervical cancer cell lines mapped by in situ hybridization,//Med.Microbiol. Immunol., 1987,v. 176,p.245-256.
2. Anceschi M.M.,Falcinelli M., Pieretti M. and Cosmi E.Y.,Multi primer pairs polymerase chaine reaction for the detection of human papillomavirus types//!. Virol.Methods, 1990,28,p.59-66.
3. Antinore M., Birrer M., Patel D., Nader L., and McCance D., The human papillomavirus type 16 E7 gene product interacts with and trans-activated the API family of transcription factors, //EMBO J.,1996,v.l5,p.l950-1960.
4. Arnott S.,Chandrasecarn R.,Hall I.H.,Puigjaner L.C.,Heteronomouse DNA,// Nucleid Acids Research, 1983 ,v. 11 ,p.4141 -415 5.
5. Baker C.C.,Phelps W.C., Lindgren V., Braun M.J., Gonda M.A. and Howley P.MStructural and transcriptional analysis of human papillomavirus 16 sequences in cervical carcinoma cell lines//.Wyo\., 1987,61,p.962-971.
6. Band V. ,Loss of p53 protein in human papillomavirus type 16 Ed-immortalized human mammary epithelial cells// J Virol. 1991 Dec;65(12):6671-6766.
7. Bedell M,. Jones K., Grossman S., and Laimons L., Identification of human papillomavirus type 18 transforming gened in immortalazed and primary cells, //J.Virol.,1989,v.63,p,1247-1255.
8. Begg A.C.,Hofland I.,Van Glabekke M.,Bartelink H., \-\ox\oii .C.Predictive value of potential doubling time for radiotherapy of head and neck tumor patients:results from the EORTC Cooperative trial 22851//Semin.Radiat.Oncol., 1992,2,p.22-25.
9. Bargmann C.I., Heung M.-V.,Weinberg R.A.,Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of pl85//Cell. 1986 Jun 6;45(5):649-57.
10. Bhuvarahamurthy V.,.Effect of radiotherapy and chemoradiotherapy on circulating antioxidant system of human uterine cerivcal carcinoma//Mo\Qcu\ar and cellular biochemistry, 1996,15 8(1),p. 17-23.
11. Bollag W.,Apfel C., LeMotte V.,Retinoids:achievements,prospectives and future go<a/,^//Differentiation Therapy,Challenges of Modern Medicine, 1995,vol. 10,p.285-302,Rome:Ares-Serono Symposia Publications.
12. Bollag W.,Isnardi L.,Jablonska S.,Klaus M., Majewski S.,Pirson W., Toma S.,Links between pharmacological properties of retinoids and nuclear retinoid receptors//Int.J.Cancer, 1997,70,p.470-472.
13. Botstein D., White R.L. et al., Construction of genetic linkage map in man using Restriction Fragment Lenghth Polymorphisms, //Amer. J. Hum.Genet.,1980,v.32,p.314-331.
14. Bouvard V.,Storey A.,Pirn D. and Banks L., Characterization of the human papillomavirus E2 protein: evidence of trans-activation and transrepression in cervical keratinocytesll EMBO J. 1994 Nov 15; 13(22):5451 -9.
15. Boyer S., Wazer D.,Band V., E7 protein papillomavirus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome /?ai/zway/Cancer.Res.,1996,56,p.4620-4624.
16. Brand N, Identification of a second human retinoic acid receptor// Nature. 1988 Apr 28;332(6167):850-3.
17. Bravard A., Sabatier L., Hoffschir F.,Ricoul M.,Dutrillaux B.,SOD2: a new type of tumor supressor gene?// Int J.Cancer, 1992,5 l,p.476-480.
18. Breitburd F., Croissant O. and Orth G., ,//Cancer Cells, Cold Spring Harbor Laboratory, 1987, v.5,p.l 15-122.
19. Burkhardt A., Willingham M., Gay C.Jeang K.T. and Schlegel R., The E5 oncoprotein of bovine papillomavirus is oriented asymmetrically in Golgi and plasma raera&ra«es//Virology,1989,v.l70,p.334-339.
20. Cannizzaro L.A., Durst M., Mendez M.J., Hecht B.K., Hecht F., Regional chromosome localization of human papillomavirus integration sites near fragile sites, oncogenes and cancer chromosome breakpoints, //Cancer Gen. Cytogen.,1988,v.33,p.93-98.
21. Chen EY, Howley PM, Levinson AD, Seeburg PH, The primary structure and genetic organization of the bovine papillomavirus type 1 genome// Nature 1982 Oct 7;299(5883):529-34.
22. Chiang C.M.,Ustav M.,Stenlund A.,Ho T.F.,Brocer T.R.,Chow L.TViral El and E2 proteins support replication oh homologous and heterologus papillomavirual origins, //Proc. Nat.Acad. Sciences USA,1992,v.89.,p.5799-5803.
23. Chirgwin J.M.,Przybyla A.E.,MacDonald R.J. and Rutter WJ.isolation of biologically active ribonucleic acid from sources enriched in ribonuclease/ZBiochemistry, 1979,18(24),p.5294-5299.
24. Choo KB, Cheung WF, Liew LN, Lee HH, Han SH, Presence of catenated human papillomavirus type 16 episomes in a cervical carcinoma cell line//J.Virol. 1989 Feb;63(2):782-9. J Virol 1989 Feb;63(2):782-9
25. Choo K.B.,Lee H.H., Lie L.N.,Chong K.Y.,Chou H.FAnalysis of the unoccupied site of an integrated human papillomavirus 16 sequence in a cervical carcinoma.//W'vco\ogy, 1990,v. 178,p.621 -625.
26. Chow LT, Chow LT, Broker TR, Papillomavirus DNA replication// Intervirology. 1994;37(3-4): 150-8.
27. Church S.L.,Grant J.W., Ridnour L. A., Oberley L.W., Swanson P.E., Meitzer P.S.,Trent J.M., Increased manganese superoxide dismutase expression supresses the malignant phenotype of human melanoma cells// Proc.Natl.Acad.Sci.,USA,1993,90,p.3113-3117.
28. Ciechanover A., The ubiquitin- proteosome proteolytic pathway, //Cell, 1994,v.79,p. 13-21.
29. Clair D.K.S., Holland J.C.,Complementary DNA encoding human colon cancer manganese superoxide dismutase and the expression of its gene in human ce//s//Cancer Res.,51,1991 ,p.939-943.
30. Collins F.S., Drumm M.L., Cole J.L. et al., Constraction of a general human chromosome jumping library, with application to cystic fibrosis,// Science, 1987,v.235,p.l046-1049.
31. Couturier J.,Sastre-Garau X.,Schneider-Maunoury S., Labib A. and Orth G.,Integration of papillomavirus DNA near myc genes in genital carcinomas and its consequences for proto-oncogeneexpression,//.Virology, 1991, Aug., p.4534-453 8.
32. Crum C., Mitao R.,Levine R.and Silverstein Cervical papillomavirus segregate within morfologically distinct precancerous lesions//. Virol., 1984, 54,p.675.
33. Cullen A.P., Reid R., Campion M., Lorincz A.T. Analysis of the physical state of different human papillomavirus DNAs in intraepithelial and invasive cervical neoplasm// J. of Virology, 1991,65(2),p.606-12.
34. Czapski G.,Radiation chemistry of oxigenated aqueous solutions!IAnnu.Rev. Phys. Chem., 1971,22,p. 171-208.
35. Desaintes C., Hallez S., Van Alphen P., Burny A., Transcriptional activation of several heterologous promoters by the E6 protein of human papillomavirus type 16, //J.Virol., 1992,v.66,p.325-3333.
36. Devlin В., Krontiris T.G. , Risch N., Population genetics of the HRAS/Minisatellite locus, //Am.J. Hum. Genet., 1993,v.53,p.l298-1305.
37. DiPaolo J A, Popescu NC, Woodworth CD, Zimonjic DB, Papillomaviruses and potential copathogensll Toxicol Lett .,1996 Nov;88 (1-3):1-7.
38. Doorbar J., Campbell D.,Grand R.J.A. and Gallimore P.H., Identification of the human papilloma virus-la E4 gene products,//EMBO J., 1986,v.5,p.355-362.
39. Doorbar J., Parton A., Hartley K., Banks L., Crook Т., Stanley M., Crawford L. Detection of novel splicing patterns in a HPV16-containing keratinocyte cell line.,//Virology,1990,v. 178,p.254-262.
40. Durst M., Gissman H., Ikenberg H. and zur Hausen H., A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions/ZProc. Natl. Acad. Sci.,1985v.80,p.3812.
41. Durst M, Dzarlieva-Petrusevska RT, Boukamp P, Fusenig NE, Gissmann L.,Molecular and cytogenetic analysis of immortalized human primary keratinocytes obtained after transfection with human papillomavirus type 16 ZW4//Oncogene, 1987;v.l, p.,251-256.
42. Durst M., Croce C.M., Gissmann L., Schwarz E., Huebner K., Papillomavirus sequences integrate near cellular oncogenes in some cervical carcinomas, //Proc.Natl.Acad.Sci. USA, 1987,v.84,p. 1070-1074.
43. El-Deiry W.,Tokino T.,Velculesen V., Levy D., Parsons R., Trent J., Lin D., Mercer W., Kinzler K.,Vogelstein B.,WAF1, a potential mediator of p53 tumor supressionjl Cell.1993.V.75.p.817-825.
44. Elbel M.,Carl S.,Spaderma S.,International Papillomavirus Workshop, 15th: Abstracts-Brisbane, 1996,p. 171.
45. Evander M.,Wedell G.yAgeneral primer pair for amplification and detection of human papillomavirus types//. Virol. Methods,1991,31,p.243-250.
46. Evans R.M ,,The steroid and thyroid hormone receptor superfamily/ZSciencQ (Washington DC),1988,240,p.889-895.
47. Felix JC, Cote RJ, Kramer EE, Saigo P, Goldman GH., Carcinomas of Bartholin's gland. Histogenesis and the etiological role of human papillomavirus///American J. Pathol.,1993,v. 142,p.925-933.
48. Fox J.L., Hsu P.H., Legator M.S., et al. Microsatellite instability in human cancer,//ClinChem., 1995, v.41,p.1554-49.
49. Frangioni J.V., Moghal N.,Stuart-Tilley A.,Neel B.C.,Alper S.L.,The DNA binding domain of retinoic acid receptor /3 is required for ligand-dependent supression of proliferation//.Cell Sci., 1994,107,p.827-838.
50. Frohman M.A.,Dush M.K. and Martin G.RRapid production of full-tength c-Ui\A jrom rare transcripts: amplification using a single gene-specific oligonucleotide primer//Proc. Natl. Acad. Sci. USA, 1988,85,p.8998-9002.
51. Garrido F.,Cabera T.,Concha A., Glew S.S., Ruiz-Cabello F., Stern P.L., Natural history of HLA expression during tumour development,//
52. Gissmann L., Durst M., Oltersdorf T., Von Knebel Doeberitz M., Human papillomaviruses and cervical cancer// Cancer Cells, 1987,5,p. 275-280.
53. Green S.,Chambon V.,Nuclear receptors enhance our understanding of transcription regM/ai/o«//TrendsGenet.,1988,4,p.309-314.
54. Gress T.M., Muller-Pillasch F., Geng M., Zimmerhackl F., Zehetner G., Fness H., Buchler M., Adler G. and Lehrach H., A pancreatic cancer-specific expression profile //Oncogene, 1996,v.13,p.1819-1830.
55. Gruis N. A., Abeln E.C., Bardoel E.F., Deville P., Frants R. and Cornellisse C.J., PCR based microsatellite polymorphism in the detection of loss of geterozyhosity in the fresh and archival tumor tissue, //Br.J.Cancer, 1993,v.68,p.308-313.
56. Gudas L.J.,Sporn M.B.,Roberts A.BCellular biology and biochemistry of the retinoids// The Retinoids: Biology, Chemistry and Medicine, 1994, p.443-520.
57. Halbert C.,Demers G., Galloway D,,The E6 and E7 genes papillomavirus type 6 have weak immortalizing activity in human epithelial cells//.J.Virol., 1992,5,p.2125-2134.
58. Hawley-Nelson P., Vousden K., Hubbert N., Lowy D.R., Schiller J.T., IIP V 16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes, //EMBO J.,1989,v.8, p.3905-3910.
59. Hernandez-Ramon E.,Villegas N.,Salcedo M.,Gariglio P. and Berumen L,The genome of HPV16 was found integrated beside a human endogenous retrovirus in cervical cancer sample//\l-ih International Papillomavirus Conference, 1999,p.418.
60. Hoffman B.,Lehmann J.M.,Zhang X.-K.,Hermann T., Husmann M.,Graupner G., Pfahl M.A retinoic acid receptor-specific element controls the retinoic acid receptor-¡3 /?rowofer//,Mol.Endocrinol.,1990.,4.,p.l727-1736.
61. Hofker M.M., Bergen A.A., Skraastad M.I., et al., Isolation of a random cosmid clone cX5, which defines a new polymorphic locus DXS 148 near the locus for Duchenne muscular dystrophy,!7 Hum.Genet.,1986,v.74,p.275-279.
62. HofmannC.,Eichele G. Retinoids in development//The Retinoids: Biology, Chemistry and Medicine, 1994,p.3 87- 442.
63. Holt S.E., Schuller G., Wilson V.G., DNA binding specificity of the bovine papillomavirus El protein is determined by sequences contained within an 18-base-pair inverted repeat element at the origin of replication,//J.Virology, 1994,v.68,p. 1094-1102.
64. Houle B.,Rochette-Engly C.,Bradley W.E.C.,Tumor-suppressive effect of the retinoic acid receptor /3 in human epidermoid lung cancer ce//s//Proc.Natl. Acad.Sci.,USA,1993,90,p.985-989.
65. Hu L.,Crowe D.L.,Rheinwald J.G.,Chambon P.,Gudas L.J .^Abnormal expression of retinoic acid receptors and keratin 19 by human oral and epidermal squamous cell carcinoma cell lines/ZCancQY Res.,1991,51,p.3972-3981.
66. Huang Y.,Peng J., G berieyL.W.,DornannF.E.,Transcripiional inhibition of manganese superoxide dismutase (SOD2) gene expression by DNA methylation of the 5'CpG island// Free Radic Biol. Med., 1997,23(2),p.314-320.
67. Hwang E.S., Nottoli T. and DiMaio D., The HPV16 E5 protein: expression, detection, and stable complex formation with /rawsmembrane proteins in COS cells,//Virology, 1995,v.21 l,p.227-233.
68. IkenbergH.,RungeM.,GoppingerA., Pfleiderer A Human papillomavirus DNA in invasive carcinoma of the vagina//Obstetr.Gynecol., 1990,vol.76,p. 432-438.
69. Ishikawa M.,Yaginuma Y.,Hayashi H., Shimizu T.,Endo Y.,TaniguchiNReactivity of a monoclonal antibody to manganese superoxide dismutase with human ovarian carcinoma!/Cancer Res.,1990,50,p.2538-2542.
70. Joenje H.,Eriksson A.W.,Frants R.R.,Arwert F.,Houwen B.,Erythrocyte superoxide dismutase deficiency in Fanconi's anaemia// Lancet, 1978, l,p.204.
71. Kahn T., Turazza E.,Ojeda R., Bercovich A.,Stremlau A., et al,Integration of human papillomavirus type 6a DNA in a tonsillar carcinoma: Cromosomal localization and nucleotide sequence of the genomic target region,// Cancer Res., 1994,v.54,p. 1305-1312.
72. Kailioniemi OP, Visakorpi T, Holli K, Isoia JJ, Rabinovitch PS Automated peak detection and cell cycle analysis of flow cytometric DNA histograms// Cytometry, 1994 Jul l;16(3):250-5
73. Kannan P, Buettner R, Pratt DR, Tainsky MA Identification of a retinoic acid-inducible endogenous retroviral transcript in the human teratocarcinoma-derived cell line PA-J // J Virol ,1991 Nov;65(l l):6343-8.
74. Kersemakers A. M. F.,Keneter G.G.,Hermans J., Fleuren G.J.,van de YijveryAllelic loss and prognosis in carcinoma of the uterine cervix!I Int. J. cancer (Pred. oncol.) 1998,79,p.411-417.
75. Kinoshita T.,Shirasawa H.,Shino Y., Moria H., Desbarats L., Eilee ML, Simiz B., Trans activation of prothymosin a and c-myc promoters by human papillomavirus type 16 E6protein, //Virology, 1997,v.232,p.53-61.
76. Kiviat N. B., Koutsky L.A., Critchlow C.W.,Lorincz A.T., Cullen A. P.,Xif'\J;J.,:vV'* J. uiivi Jl i:JiiiiCS i'v.i'V.// JLiiL. J. Ojfj-lwCOi. I^ciLiiOi. ? i v V . I i i y / " — w
77. Klingelhutz A., Foster S., McDougall .,Telomerase activation by the E6 gene product of human papillomavirus type 16, //Nature, 1996,v.380,p.529-531.
78. Khare S.,Pater M.M.,Pater A., Role of exogenous cofactors in HPV infection and oncngenesis//Papillomavirus Report, 1995,6,p.89-93.
79. Kok K, Naylor SL, Buys CH, Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes// Adv Cancer Res 1997; 71:p. 27-92
80. Krontiris T.G. , Devlin B., Karp D.D.,Robert N.G., Risch N., An association betwen the risk of cancer and mutations in the HRASI minisatellite /ocM^//Ni.Engl.J.Med.,1993,v.329,pp.517-23.
81. Kurz J.,Mitra K.,Adam R.,Miao X., MacKay J.S.,Isa N.N.,Coombs D.H.,Krause M.O., PCR detection and typing of genital papillomavirus in New Brunswick population,Int.. Cancer., 1993,55y4, p.604-608.
82. Laird C.,Jaffe E.,Karpen G.,Lamb M.,Nelson R., Fragile sites in human chromosomes as regions of late-replicating DNA, //Trend Genet., 1987, v.3,p.274-281.
83. Lambert PF, Pan H, Pitot HC, Liem A, Jackson M, Griep AE., Epidermal cancer associated with expression of human papillomavirus type 16 E6 andE7 oncogenes in the skin of transgenic mice// Proc. Natl Acad. Scl, U S A, 1993 Jun 15;90(12):5583-7.
84. Lazo P., DiPaolo J.A., Popescu N.C., Amplification of viral transforming genes of human papillomavirus-18 and 5'flanking sequences located near myc proto-oncogene in HeLa cells,//Cancer Res., 1989.
85. Liang P.,Averboukh L. and Pardee A.B., Distribution and cloning of eukaryotic mRNAs by means of differential display, refinements and optimization//Nucleic Acids Res., 1993,v.21,p.3269-3275.
86. Lopezborges S., Gallego M.I., Lazo P.A., Recurrent integration of papillomavirus DNA within the human 12ql4-15 uterine breakpoint region in genital carcinomas II Genes, Chromosomes and Cancer,1998,Sep.,v.23(l),p.55-60.
87. Lotan R., Xu X-C.,Lippman S.M., Ro J.Y., Lee J.S., Lee J.J., Hong W.K.,Supression of retinoic acid receptor (3 in premalignant oral lesions and its up-regulation by isotretinoin//N.Engl.J.Med.,1995,332,p.1405-1410.
88. Mack DH, Laimins LA., A keratinocyte-specific transcription factor, KRF-1, interacts with AP-1 to activate expression of human papillomavirus type 18 in squamous epithelial cells/1 Proc. Natl. Acad. Sci. USA., 1991, 88, p.9102-9106.
89. Mandel M., Niga A.,Calcium deendent bacteriophage DNA infection//}. Mol. Biol., 1970,53,p.154.
90. Mansur CP, Androphy EJ., Cellular transformation by papillomavirus oncoproteins,/IBB A, 1993, v. 115 5 ,p. 3 23 -3 45.
91. Matlashewski G., Schneider J., Banks L., Jones N.,Murray A., Crawford L., Human papillomavirus type 16 DNA cooperates with activated ras in transforming primary cells, //EMBO,J., 1987,v.6,p.1741-1746.
92. Matsukura T, Koi S.,Sugase M ,,Both episomal and integrated forms of human papillomavirus type 16 are involved in invasive cervical cancers// Virology, 1989,v. 172,p.63-72.
93. Mazurenko N., Attaleb M., Gritsko T., Semjonova L., Pavlova L., Sakharova O. and Kisseljov F.,High resolution mapping of chromosoma 6 deletions in cervical cancer//Oncology Reports, 1999,6,p. 1-5.
94. Mazurenko N., Guo Z.,Attaleb M.,Hu X., Semjonova L., Sakharova O.Kisseljov F. and Ponten l.,High iricedence of homogenouse allelic loss at 6ql6.3-21 in microdissected cervical ca/7cer//'Cancer Res., 1999,in press
95. Mazzarelli J., Atkins G., Geisberg J.,Ricciardi R., HThe viral oncoproteins Ad5,ElA,HPV 16 and SV 40 Tag bind a common region of the TBR- associated factor-110// Oncogene, 1995,v. 11 ,p. 1859-1864.
96. McCord J.M., Fridovich I.Superoxide dismutase an enzymic funcion for erythrocuprein (hemocuprein) //,J.Biol.Chem., 1969,244,p.6049-6055.
97. Mclntyre M., Ruesch M., Laimins L., Human papillomavirus E7 oncoproteins bind a singli form of eye I in in a com I ex with cdk2 and pi 07, //Virology, 1996,v.215,p.73-83.
98. McNally N,.,Can cell kinetic parameters predict the response of tumours to radiotherapy?/AntJ.Radiai.Biol.,1989,56,p.777-786.
99. Merril CR, Dunau ML, Goldman Dy4 rapid sensitive silver stain for polypeptides in polyacrylamide gels// Anal Biochem 1981 Jan l;110(l):p.201-207
100. Miyashita T., Reed J. C., Tumor suppressor p53 is a direct transcri ptional activator of the human bax gene//Cell,1995,v.80,p.293-299.
101. Mitra A.B., Rao P.H. and Pratap M.J(5p) and del (6q) are nonrandom abnormalities in carcinoma cervix uteri/ZCancer Genet. Cytogenet.,1994,76,p.56-58.
102. Muir C., Waterhause J.,Mack T.,Powell J.,Whelan S.,Cancer incidence in five continents// \ARC\Lyon,\9%1
103. Mullokandov M.R.,Kholodilov N.G.,Atkin N.B., Burk R.D., Johnson A.B., Klinger H.PGenomic alterations in cervical carcinoma: losses of chromosome heterozygosity and human papilloma virus tumor status// Cancer Res., 1996,56,p. 197-205.
104. Munger K., Phelps W., Bubb V., Howley P., Schlegel R., The E6 andE7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes, //J.Virol., 1989,v.63 .p.4417-4421.
105. Nakano T.,Oka K.,Differential value of growth fraction and mitotic index of proliferating population of cervical cancer/ZCanccv (Phila.),1993,72,p.2401-2408.
106. Nakano T.,Oka K.,Taniguchi N.,.Manganese superoxide dismutase expression correlates with p53 status and lokal recurrence of cervical carcinoma treated with radiation therapy/ZCancer Res., 1996,56,p.2771-2775.
107. Neary K., Horwitz B.H. and DiMaio D., Mutational analysis of open reading /rame E4 of bovine papillomavirus type 1,//J. Virology, 1987, v. 61 ,p. 1248-1252.
108. Nees M., van Wijngaarden E., Bakos E., Schneider A., Durst M., Identification of novel molecular markers which correlate with HPV-induced tumor progression, //Oncogene, 1998,v. 16,p.2447-2458.
109. Nürnberg W., Artuc M., Nawrath M., Lovric J.,Stuting S.,Moelling K., Czarnetzki B.M., Schadendorf D,Human c-myb is expressed in cervical carcinomas and trans activates the HPV-16 promoter// Cancer Res.,1995,Oct.,55 (19),p.4432-4437.
110. O'Hara B.,Klinger P.H.,Blair D.C.,Many oncogenes are transcribed in the D98AH2 derivative of the HeLa carcinoma cell line//Cytogenet.Cell.Genet., 1986,43 ,p.97-102.
111. Oberley L.W.,Buettner G.R,,Role of superoxide dismutase incancer: a review/ZCancQY Res.,1979,39,p.l 141-1149.
112. Oberley L.W., St.Clair D.K.,Autor A.P.,Oberley T.DIncrease in manganese superoxide dismutase activity in the mouse heart after X-irradiation//Arch.Biochem. Biophys., 1987,254,p.69-80.
113. Ohozono T.,Ishiguro N., Horiuchi M., ShinagawaM., Potential transforming-ability by internal deletion of the bovine c-myb gene// J. Vet. Med.Sci.,1996,Apr.58 (4),p.305-310.
114. Pan H.,Griep A.,Temporally distinct patterns of p53-dependent andp53 independent apoptosis during mouse lens development, II Genes. Dev., 1995,v.9,p.2157-2169.
115. Phelps W.C. and Howley P.M., Transcriptional trans-activation by the human papillomavirus type 16 E2 gene product.,//J. Virology, 1987, v. 61 ,p. 163 0-163 8.
116. Pirami L. ,Giache V.,Becciolini A., Analysis of HPV 16,18,31 and35 DNA in pre-invasive and invasive lesions of the uterine cervix, //J.of Clinical Pathology, 1997,v.50(7),p.600-604.
117. Pirisi L, Yasumoto S, Feller M, Doniger J, DiPaolo JA., Transformation of human fibroblasts and keratinocytes with human papillomavirus type 16 DNAIIi:Virology, 1987,v. 61 ,p. 1061 -1066.
118. Ponten J.,Adami H.O.,Friberg L.G.,Gustafsson L.,MillerA.B.,?arkinM,,Sparen P. and Trtchopoulos D., HPV and cervical cancer.//int. J. Cancer, 1995,63,p.317
119. Popescu N.C.,DiPaolo J.A.,Amsbaugh S.C., Integration sites of human papillomavirus 18 DNA sequences on HeLa cell chromosomes, //Cyt.Cell Gen.,1987,v.44,p.58-62.
120. Popescu N., DiPaolo J.A., Preferential sites for viral integration on mammalian genome,//Cane. Gen. Cytogen.,1989,v.42,p. 157-171.
121. Prabhu N.S., Somasundram K.,Satyamoorthy K., Heryn M. and El-Deiry W.S., et d\.,P73/3, unlike p53, suppresses growth and induces apoptosis of human papillomavirus E6 expressing cancer cells// Inter J.Oncol., 1998,13 ,p.5-9.
122. Putenveetti J.,Frederickson S., KQzmkoif,Apoptosis in human papillomavirus 16 E7,but not E6 immortalized human ureoepitelial ce//^//Oncogene, 1996,13,p. 1123-1131.
123. Rader J.S., Kakarasova T.,Huettener P.C., Li L., Li Y. and Gerhard D.S., Allelotyping of all chromosomal arms in invasive cervical cancer/ZOncogeriQ, 1996,13 ,p.2737-2741.
124. Rohdewohld H.,Reik W.,Jaenish R.,Breindl M.,Retroviurs integration and chromatin structure: Moloney murine leukemia proviral integration sites map near DNase-hypersensitive sites,II J.of Virol.,1987,v.61,p.336-343.
125. Rosl F.,Arab A.,Klevenz B. and zur Hausen H., The effect of DNA methylation on gene regulation of human papillomaviruses,//.I.genVirol., 1993 ,v.74,p.791 -801.
126. Safford SE, Oberley TD, Urano M, St Clair DK, Suppression of fibrosarcoma metastasis by elevated expression of manganese superoxide dismutase, //Cancer Res 1994 Aug 15;54(16):4261-5.
127. Sager R., Expression genetics in cancer: shifting the focus from DNA to RNA,//Proc.Natl.Acad.Sci.USA, 1997,v.94,p.952-955.
128. SamoilovaE.,ShaichaevG.,KisseljovF.,//PK infection in cervical-cancer cases in Russiall Int.J.Cancer, 1995,v.61,p.337-342.
129. Sasaki T.,Sakka M. ,Implications of thymidine labeling index in the growth kinetics of human solid tumors// Jpn.J.Cancer Res.,1981,72,p. 181188.
130. Scheffner M., Werness B., Huibregste J., Levine A.J., Howley P.M. The E6 oncoprotein encoded by human papillomavirus type 16 and 18 promoters the degradation ofp 53, //Cell. 1990,v.63,p. 1129-1136.
131. Schwaiger H.,Weirich H.G.,Brunner P.,Rass C., Hirsch-KauffmanM.,Groner Y.,Schwaiger M. Radiation sensitivity of Down's syndrome fibroblasts might be due to overexpressed Cu/Zn-superoxide dismutase//Em.J.Cq\\ Biol., 1989,48,p.79-87.
132. Schwarz E., Freese U.K., Gissmann L.Structure and transcription of human papillomavirus sequences in cervical carcinoma ce//s//Nature, 1985,314,p. 111-114.
133. Shamanin V.,Delius H. and de Villiers E.M.Development of a broad spectrum PCR assay for papillomaviruses and its application in screening lung cancer biopsies//J. Gen. Virol., 1994,75,p. 1149-1156.
134. Shon E., Evans T., Welsh H.,Estratiadis A., Conformation of promoter DNA : fine mapping of SI-hypersensitive sites, //Nucleid Acids Research, 1983 ,v. 19,p.7201 -7205.
135. Singal P.K.,Petkau A.,Gerrard J.M., Hrushovetz S., Foerster J.,Free radicals in health and diseased, Mol.Cell.Biochem., 1988,84, p. 121-122.
136. Stoler M.H., Rhodes C.R.,Whitbeck A.,Wolinsky S.M.,Chow L.T.,Broker T.R., Human papillomavirustype 16 and 18 gene expression in cervical neoplasias, //Human Pathology, 1992,v.23(2), p. 117-28.
137. Stoppler MC, Ching K, Stoppler H, Clancy K, Schlegel R., Natural variants of the human papillomavirus type 16 E6 protein differ in their abilities to alter keratinocyte differentiation and to induce p53 degradation// J .Virol .1996 C)ct;70(10):6987-93
138. Storey A, Banks L., Human papillomavirus type 16 E6 gene cooperates with EJ-ras to immortalize primary mouse cells,// Oncogene 1993 Apr;8(4):919-24.
139. Sucov H.M.,Murakami K.K.,Evans R.M.,Characterization of an autoregulated response element in the mouse retinoic acid receptor (3 gene//?roc. Natl.Acad.Sci.USA,1990,87,p.5392-5396.
140. Sverdrup F. and Khan S.A., Replication of human papillomavirus (HPV) DNAs supported by the HPV type 18 El and E2 proteins,//J.Virology,1994, v.68,p.505-509.
141. Swisshelm K.,Ryan K., Lee X.,Tsou H.C., Peacocke M.,Sager K.,Down-regulation of retinoic acid receptor ft in mammary carcinoma cell lines and its up-regulation in senescing normal mammary epithelial cells//Cell Growth & Differ., 1994,5,p.133-141.
142. Taichman L.B. and La Porta R.F.The Papovaviridae, Plenum,New York, 1984,v.2,p. 109-139.
143. Thomilinson,Gray L.H.,The histological structure of some human lung cancers and possible implications for radiotherapy/Air. J. Cancer, 1955,9,p.539-549.
144. Ting Y., Manos M.,Detection and typing of general human papillomaviruses in PCR protocols:A guide to methods and application// Academic Press Inc., 1990,p.356-367.
145. Tommasino M., Adamczewski J., Cariotti F., Barth C.F., Manetti R., Contorni M., Cavalieri F., Hunt T., Crawford L. Proteine assotiates with the proteine kinasep33 CDK2 and cyclin A.J!Oncogene,1993,v.8,p. 195-202.
146. Tsao S., Mok S., Fey E., Characterization of human ovarian surface epithelial cells immortalized by human papillomaviral oncogenes (HPV-E6E7 ORFs), //Exp.Cell. Res.,1995,v.218, p.499-507.
147. Turc-Carel C., Pietrzak E., Kakati S., Kinniburgh A.J., Sandberg A.A., The human int-1 gene is located at chromosome region 12ql2-12ql3 and is not rearranged in myxoid liposarcoma with t(12:16)(ql3:p 1 /^//Oncogene Res.,1987,v.l,p.397-405.
148. Unger E.R.,Vernon S.D., Thorns W.W., Nisenbaum R., Spann C.O., Horrowitz I.R., Icenogle J.P., Reeves W.C., Human papillomavirus and disease free survival in FIGO stage lb cervical cancer, //J.Infect.Dis., 1995,v. 172, p.l 184-1190.
149. Urano M.,Kuroda M,.ReynoldsR.,OberleyT.D.,St.Clair D. K.Expression of manganesesuperoxide dismutase reduces tumor control radiation dose:gene-radiotherapy//Cancer Res.,1995,55,p.2490-2493.
150. Vajaya S.,Steffen D.L.,Robinson H.L.^Acceptor sites for retroviral integrations map near DNasel-hypersensitive sites in chromatin, //J. of Vir., 1986,v.60,p.683-692.
151. Van den Brule A.J.C., Snijders P.J.F. and Walboomers J.M.PCR-based detection of genital HPV genetypes: an updateand future perspectives/ZPapillomaviYus Report, 1993,4,p.95-99.
152. Veres G. R.A., Scherer S.E. and Caskey C.T.The molecular basis of the sparse for mouse rawfaizo«//Science,1987,237,p.415-417.
153. Vernon S.D., Unger E.R., Miller D.L., Lee D.R., Reeves W.C., Assotiation of human papillomavirus type 16 integration in the E2 gene with poor disease-free survival from cervical cancer, //Int. J.Cancer, 1997,v.74,p.50-56.
154. Villaume M.,Calvayrac R.,Best-Belpomme M.,Tarroux P.,Hubert M.,Decroix Y.,Sarasain A.,Deficiency in the catalase activity of xeroderma pigmentosum cell and simian virus 40-transformed human cell extracts/ZConcQV Res., 1986,46,53 8-544.
155. Wagatsuma M.,Hashimoto K., Matsukura Т.,Analysis of integrated human papillomavirus type 16 DNA in cervical cancers: amplification of viral sequences together with cellular flancing sequences, II J. Virology, 1990,v.64(2),p.813-21.
156. Wank R, Thomssen C., High risk of squamous cell carcinoma of the cervix for women with HLA-DQw3,// Nature ,1991 Aug 22;352(6337):723-5.
157. Wazer D., Liu X., Chu Q., Gao Q. and Band V., Immortalization of distinct human mammary epithelial cell types by human papillomavirus 16 E6 or E7JIYVOC. Nat. Acad.Sci.USA,1995, v.92, p.3687-3691.
158. Weinberg R., The retinoblastoma protein and cell cycle control, //Cell,1995,v.81,p.323-330.
159. Wentzensen N., 1999,17-th International Papillomavirus Conference, неопубликованные данные.
160. White A., Livanos E., Tlsty T., Differential distruption of genomic integrity and cell cycle regulation in normal human fibroblasts by the HPV oncoproteins JI Genes and Dev., 1994,v.8, p.667-677.
161. Wilczynski S.P., Pearlman L. and Walker J .Identification of HPV 16 early genes retained in cervical carcinomas/Nivology, 1988,166,p.624-627.
162. Xu X-C.,Ro J.Y.,Lee J.S.,Shin D.M.,Hong W.K.,Lotan R.,Differential expression of nuclear retinoid receptors in normal, premalignant and malignant head and neck tissues/ZCancer Res.,1994,54,p.3580-3587.
163. Yokota J.,Tsukada Y.,Nakajima T.,Gotoh M.,Shimosato Y.,Mori N.,Tsunokawa Y.,SugiromaT.,Terada M^Loss of heterozygosity on the short arm of chromosome 3 in carcinoma of the uterine cervix// Cancer Res.,1989,49,p.3598-3601.
164. Zhang X-K.,Liu Y.,Lee M.-0.,Pfahl M. A specific defect in the retinoic acid response assosiated with human lung cancer cell /mesV/Cancer Res., 1994.,54,p.5663-5669.
165. Zimonjic D.B.,Popescu N.D.,DiPaolo J.A.,Chromosomal organization of viral integration sites in human papillomavirus immortalized human keratinocyte cell lines,//Cane. Gen. Cytogen.,1994.,v.72(l),p.39-43.
166. Zunback et al.,Int.J.Cancer,in press, 1999
167. Zur Hausen H., Condylomata acuminata and human genital cancer, //Cancer Res., 1976,v.36,p.530.
168. Zur Hausen H., Intracellular surveillance of persisting viral infections. Human genital cancer results from deficient cellular control of papillomavirus gene expression,//Lancet, 1986,2 ,p.489-491.
169. Zut Hausen H., Disrupted dichotomous intracellular control of human papillomavirus infection in cancer of the cervix,//Lancet,1994,v.343,p.955-957.
170. Zur Hausen H., Papillomavirus infections- a major cause of human cancers,//BB A, 1996,v. 1288,p.55-78.
171. Бюл. WHO Press Release, Cervical Cancer: Этиологическая роль HPV при раке шейки матки ,//WHO/47, 1996,July 3.
172. Киселев Ф. Л.,Вирусы папиллом человека как этиологический фактор при раке шейки матки: значение для практики здравоохранения //Вопросы вирусологии, 1997,6,стр.248-251.