Автореферат и диссертация по медицине (14.00.14) на тему:Исследованиe p53-зависимых сигнальных путей, ответственных за поддержание целостности генома
- Ученая степень
- кандидата биологических наук
- ВАК РФ
- 14.00.14
Оглавление диссертации Туровец, Николай Александрович :: 1999 :: Москва
Введение.
Глава 1. Обзор литературы.
Введение.
1.1. Нарушения функции р53 в новообразованиях человека
1.2. Структура и биохимические активности р53.
1.3. Механизмы активации р53 при стрессовых воздействиях.
1.3.1. Способы регуляции активностей р53.
••«.'•* • ' Ч
1.3.2. Пути передачи сигнала при различных повреждающих и стрессовых воздействиях.
1.4. Кофакторы транскрипционной активности р53: опухолевый супрессор рЗЗ 114101.
1.5. Роль р53 в регуляции апоптоза.
1.6. Роль р53 в регуляции сверочных точек клеточного цикла.
1.6.1. Сверочные точки клеточного цикла.
1.6.2. Роль р53 в регуляции сверочной точки в 01.
1.6.3. Роль р53 в регуляции сверочной точки в 02.
1.7. Нестабильность генома при нарушениях функции р53.
Введение диссертации по теме "Онкология", Туровец, Николай Александрович, автореферат
Актуальность проблемы. Генетическая нестабильность - характерная черта неопластических клеток, предопределяющая неуклонную прогрессию опухолей, выражающуюся в появлении и отборе все более и более агрессивных клонов. Убедительно продемонстрировано, что ключевую роль в возникновении генетической нестабильности в неопластических клетках могут играть нарушения функции опухолевого супрессора р53, мутации которого являются самым частым генетическим изменением в различных новообразованиях человека. Физиологическая функция этого белка, являющегося транскрипционным фактором, заключается в предотвращении пролиферации клеток, в которых уже произошли или еще только могут произойти генетические изменения. В основе такой активности р53 лежит его способность активироваться при самых разных внутриклеточных аномалиях и вызывать в ответ на их возникновение либо остановку клеточного цикла в определенных его точках (т.н. чекпойнтах или "сверочных точках"), либо апоптоз (программируемую гибель клеток). Нарушение охранной функции р53 резко увеличивает скорость накопления клеток с самыми разными изменениями генома: разрывами и рекомбинациями хромосом, изменениями числа хромосом, амплификацией генов и, как следствие, резко повышает вероятность развития новообразований. Однако до сих пор остается неясной роль отдельных элементов сигнальных путей, контролируемых р53, в поддержании генетической стабильности.
Цель и задачи исследования. Целью настоящей работы являлось изучение роли отдельных элементов сигнальных путей р53 в контроле генетической стабильности. Было запланировано решение следующих экспериментальных задач:
1. Провести сравнительное исследование влияния гомозиготного нокаута генов p21WAF1 (мишень трансактивационного действия р53), pRb (мишень p21 waf1} и pl9ARF (обеспечивает активацию р53 при некоторых аномалиях) на функциональную активность сверочных точек клеточного цикла, регуляцию индукции апоптоза при повреждениях ДНК и частоту возникновения числовых и структурных изменений хромосом в культивируемых in vitro мышиных эмбриональных фибробластах.
2. Изучить генетические последствия подавления в клетках человека и крысы функции недавно идентифицированного опухолевого супрессора рЗЗш01■ -кофактора транскрипционной активности р53.
Научная новизна и практическая значимость работы. Показано, что инактивация генов р53, p21WAFl, INK4a/ARF или Rb ослабляет эффективность работы сверочной точки клеточного цикла в G1 и значительно увеличивает частоту изменений кариотипа в пролиферирующих клетках. При этом продемонстрировано, что степень генетической нестабильности при нокауте указанных генов неодинакова: наибольшая частота спонтанных и индуцированных изменений хромосом наблюдается при инактивации гена р53, а наименьшая - при нокауте гена Rb. Обнаружено, что уровень хромосомной нестабильности в клетках с инактивированной функцией сверочной точки в G1 зависит от степени подавления в них реакций апоптоза, индуцируемых мутагенными воздействиями. Впервые показано, что трансдукция в р53-позитивные крысиные и человеческие клетки генетического супрессорного 7 элемента рЭЗ-ОБЕаэ, понижающего экспрессию рЗЗ0^01, ослабляет эффективность работы сверочных точек клеточного цикла в и Б, и повышает частоту разрывов хромосом, сестринских хроматидных обменов и изменений копийности генов. Показано, что генетические последствия трансдукции рЗЗ-ОБЕаэ, ингибирующего экспрессию рЗЗШ01, не отличаются от эффектов, наблюдаемых при трансдукции р53-08Е22, подавляющего транскрипционные активности р53 по доминантно-негативному механизму.
Результаты проведенной работы способствуют лучшему пониманию механизмов опухолевой прогрессии, что является важным для создания принципиально новых методов лечения злокачественных новообразований.
Заключение диссертационного исследования на тему "Исследованиe p53-зависимых сигнальных путей, ответственных за поддержание целостности генома"
выводы
1. Исследовано влияние инактивации генов р53, p21WAF1, pRb, pi9ARF и рЗЗШС1 (кофактора транскрипционной активности р53) на функцию сверочных точек клеточного цикла и генетическую стабильность. Показано, что подавление активности каждого из этих генов ослабляет эффективность работы сверочной точки в G1, но не отменяет задержку поврежденных клеток в G2.
2. Инактивация генов р53, p21WAF1, pRb и р19 значительно увеличивает частоту изменений кариотипа в пролиферирующих мышиных эмбриональных фибробластах. При этом степень генетической нестабильности при нокауте указанных генов неодинакова: наибольшая частота спонтанных и индуцированных изменений хромосом наблюдается при инактивации гена р53, а наименьшая - при нокауте гена Rb.
3. В мышиных эмбриональных фибробластах с инактивированной функцией сверочной точки в G1 степень хромосомной нестабильности зависит от уровня подавления в них реакций апоптоза.
4. Трансдукция в р53-позитивные крысиные и человеческие клетки генетического супрессорного элемента рЗЗ-GSEas, понижающего экспрессию рЗЗ™01, ослабляет эффективность работы сверочной точки клеточного цикла в S.
5. Подавление активности p33rNGI увеличивает вероятность возникновения самых разных генетических нарушений: разрывов хромосом, сестринских хроматидных обменов и изменений копийности генов.
Список использованной литературы по медицине, диссертация 1999 года, Туровец, Николай Александрович
1. The Jornal of Biological Chemistry, 1998, 273, 1-4. Agoff S.N., Hou J., Lizer D.I., Wu B. Regulation of the human hsp70 promoter by p53. Science, 1993, 259, 84-87.
2. Amundson S.A., Myers T.G., Fornace A.J.Jr. Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress. Oncogene, 1998, 17, 3287-3299.
3. Arrowsmith C.H. and Morin P. New insights into p53 function from structural studies. Oncogene, 1996, 12, 1379-1385.
4. Atadja P., Wong H., Garkavtsev I., Veillette C., Riabovol K. Increased activity of p53 in senescing fibroblasts. Proc. Natl. Acad. Sci. USA, 1995, 92, 8348-8352.
5. Bakalkin G., Yakovleva T., Selivanova G., Magnusson K.P., Szekely L., Kiseleva E., Klein G., Terenius L., .and Wiman KG. p53 binds single-stranded DNA ends and catalyzes DNA renaturation and strand transfer. Proc.Natl., Acad. Sci., 1994, 91, 413-417.
6. Baker S.J.,Preisinger A.C., Jessup J.M. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res, 1990, v.50, p.7717-7722.
7. Barak Y., Juven T. Haffner R., and OrenM. mdm2 expression is induced by wild type p53 activity. EMBO J., 1993, 12,461-468.
8. Barak, Y, Gottlieb, E., Juven Gershon, T., and Oren, M. Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential. Genes Dev., 1994, 8, 1739-1749.
9. Bargonetti, J., Friedman, P.N., Kern, S.E., Vogelstein, B., andPrives, C. Wild-type but not mutant p53 immunopurified proteins bind to sequences adjacent to the SV40 origin of replication. Cell, 1991, 65,1083-1091.
10. Bayle J.H., Elenbaas B., Levine A.J. The carboxy-terminal domain of the p53 regulates sequence-specific DNA binding through its nonspecific nucleic acid-binding activity. Proc. Natl. Acad. Sci. USA, 1995, 92, 5729-5733.
11. BressacB., Kew M., Wands J., Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from Southern Africa. Nature, 1991, 350, 429-431.
12. BehamA., Marin M.C., Fernandez A., Herrmann J., Brisbay S., TariA.M., Lopez-Berestein G., Lozano G., Sarkiss M., McDonnell T.J. Bcl-2 inhibits p53 nuclear import following DNA damage. Oncogene, 1997, 15, 2767-2772.
13. Bienz-Tadmor B; Zakut-Hoari R; Libresco S; Givol D; OrenM. The 5' region of the p53 gene: evolutionary conservation and evidence for a negative regulatory element. EMBO J., 1985, 4, 3209-3213.
14. Benchimol S., Lamb P., Crawford L.V., Sheer D., Shours T.B., Brum G.A.P., Peacock J. Transformation assotiated p53 protein is encoded by a gene on human chromosome 17. Som. CellMol. Gen., 1985, v. 11, p.505 509.
15. Bertrand P., Rouillard D., Boulet A., Levalois C., Soussi T., Lopez B.S. Increase of spontaneous intrachromosomal homologous recombination in mammalian cells expressing a mutant p53 protein. Oncogene, 1997, 14, 1117-1122.
16. Bourne H.R., Sanders D.A., McCormic F. The GTPase superfamily: a concerved switch for diverse cell function. Nature, 1991, 349, 117-127.
17. Brain R. and Jenkins J.R. Human p53 directs DNA strand reassociation and is photolabelled by 8-azido ATP. Oncogene, 1994, 9, 1775-1780.
18. Buckbinder L., Talbott R., Velasco-Miguel S., Takenaka L., Faha B., Seizinger B.R., and Kley N. Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature, 1995, 377, 646-649.
19. Caelles C., Heimberg A., Karin M. p53-dependent apoptosis in the absence of p53-target genes. Nature, 1994, 370, 220-223
20. Canman C.E.; Gilmer T.M.; Coutts S.B.; Kastan, M.B. Growth factor modulation of p53-mediated growth arrest versus apoptosis. Genes Dev., 1995, 9, 600-611.
21. Carder P., Wyllie A.H., Purdie C.A., Morris R.G., White S., Piris J., Bird C C. Stabilised p53 facilitates aneuploid clonal divergence in colorectal cancer. Oncogene, 1993, v.3, p.1397-1401.
22. Caron de Fromentel C., Soussi T. The TP53 tumor suppressor gene: a model foi investigating human mutagenesis. Genes, Chromosome, Cancer, 1992, v.4 p.l 15.
23. Chen P.L., Chen Y., Bookstein R., Lee W.H. Genetic mechanisms of tumor suppression b> the human p53 gene. Science, 1990, 250, 1576-1580.
24. Chen J.-Y., Funk W.D., Wright W.E., Shay J.W., and Minna J.D. Heterogeneity of transcriptional activity of mutant p53 proteins and p53 DNA target sequences. Oncogene, 1993, 8, 2159-2166.
25. Chen X., Bargonetti J., and Prives C. p53, through p21 (WAF1/CIP1), induces cyclin D1 synthesis. Cancer Res, 1995, 55, 4257-4263.
26. Chen J., Willingham T., ShufordM., Bruce D., Rushing E., Smith Y., Nisen P.D. Effects of ectopic overexpression of p21/wafl/cipl on aneuploidy and the malignant phenotype of human brain tumor cells. Oncogene, 1996, 13, .1395-1403.
27. Chen J, Willingham T, ShufordM, Bruce D, Rushing E, Smith Y and Nisen PD. Effects of ectopic overexpression of p2lWAF1/CIP1 0n aneuploidy and the malignant phenotype of human brain tumor cells. Oncogene, 1996, 13, 1395-1403.
28. Chernov M. V. and Stark G.R. The p53 activation and apoptosis induced by DNA damage are reversibly inhibited by salicylate. Oncogene, 1997, 14, 2503-2510.
29. Chernova O.B., Chernov M.V., Agarwal M.L., Taylor W.R., Stark G.R. The role of p53 in regulating genomic stability when DNA and RNA synthesis are inhibited. Trends Biochem., 1995, 20, 431-434.
30. Chernova O., Chernov M., Ishizaka Y., Agarwal M., Stark G. MYC Abroates p53-Mediated Cell Cycle Arrest in N-(Phosphonacetyl)-L-Aspartate-Treated Cells, Permitting CAD Gene Amplification. Mol.Cell.Biol., 1998, 18, 536-545.
31. Cho , Y., Gorina S., Jeffrey P.D., and Pavletich N.P. Crystal structure of a p53 tumor suppressor-DNA complex: Understanding tumorigenic mutations. Science, 1994, 265, 346-355.
32. Chumakov A.M., Miller C.W., Chen D.L., Koeffler H.P. Analysis of p53 trans-activation through high-affinity binding-sites. Oncogene, 1993, v.8, p. 3005-3011.
33. Clarke A.R., Purdie C.A., Harrison D.J., Morris R.G., BirdC.C., HooperM.L., WyllieA.H. Thymocyte apoptosis is induced by p53-dependent and independent pathways. Nature (London), 1993, 362, 849-852.
34. Cleaver J.E. Defective repair replication of DNA in xeroderma pigmentosum. Nature, 1968, 218, 652-656.
35. Clore G.M., Ernst R., Cluhh J.G., Omichinski W.M.P., Kennedy K., Sakaguchi E., Appella E., Gronenborn A.M. Refined solution structure of the oligomerization domain of the tumor suppressor p53. Struct. Biol., 1995, 2, 321-332.
36. Cowley S., Paters on H., Kemp P., Marshall C.J. Activation of MAP kinase kinase is necessary and sufficient for PC 12 differentiation and for transformation of NIH 3T3 cells. Cell, 1994, 77, 841-852.
37. Cox, L.S., T.Hupp, C.A.Midgley, and D.P.Lane. A direct effect of activated human p53 on nuclear DNA replication. EMBOJ, 1995, 14, 2099-2105.
38. Cox L.S.; Lane D.P. Tumour suppressors, kinases and clamps: how p53 regulates the cell cycle in responce to DNA damage. BioEssays, 1995, 17, 501-508.
39. Cross S.M., Sanches CA., Morgan C.A., Schimke M.K., Ramel S., Idzerda R.L., Ras kind W.H., Reid B.J. A p53-dependent mouse spindle checkpoint. Science, 1995, v.267, p. 1353-1356.
40. Deb S., Jackson C.T., Sutler M.A., Martin D. W. Modulation of cellular and viral promoters by mutant human p53 proteins found in tumor cells. J. Virol., 1992, 66, 6164-6170.
41. Deb S.P., Munoz R.M., Brown D.R., Subler M.A., Deb S. Wild-type human p53 activates the human epidermal growth factor receptor promoter. Oncogene, 1994, 9, 1341-1349.
42. Debbas M. and White E. Wild-type p53 mediates apoptosis by El A, which is inhibited by E1B. Gene Dev., 1993, 7, 546-554.
43. Di Leonardo A., Linke S.P., Clarkin K, Wahl G.M. DNA damage triggers a prolonged p53-dependent Gl arrest and long-term induction of Cipl in normal human fibroblasts. Genes Dev. 1994, 8, 2540-2551.
44. Donehower L.A., Harvey M., Slagle B.L., Mcarthur M.J., Montgomery C.A., Butel J.S., Bradley A. Mice deficient for p53 are developmentally nirmal but susceptible to spontaneous tumours. Nature (London), 1992, 356, 215-221.
45. Donehower L.A., Bradley A. The tumor suppressor p53. Biochem.Biophys. Acta. 1993, v.1155, p. 181-205.
46. Downward J. Control of ras activation. Cacer Surv., 1996, 27, 87-100.
47. Dulic V., Kaufmann W.K., Wilson S.J., Tlsty T.D., Lees M., Harper W., Elledge S.J., Reed S.I. p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced Gl arrest. Cell, 1994, 76, 1013-1023.
48. DuttaA., Ruppert J.M., Aster J. C., Winchester E. Inhibition of DNA replication factor RPA by p53. Nature, 1993, 365, 79-82.
49. El Die*y W.S., Kern S.E., Pietenpol J.A., Kinzler K.W., Vogelstein B. Definition of a consensus binding site for p53. Nat. Genet., 1992, 1, 45-49.
50. El Deiry W.S., To kino T., Velculescu P.M., Levy D.B., Parsons B., Trent J.M., Lin D., Mercer W.E., Kinzler K.W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell, 1993, 75, 817-825.
51. Elledge S.J. Cell cycle checkpoints; preventing an identity crisis. Science, 1996, v. 274, 1664-1672.
52. Englert C., Maheswaran S., Garvin A. J., Kreidberg J., Haber D.A. Induction of p21 by the Wilms' tumor suppressor gene WT1. Cancer Res., 1997, 57, 1429-1434.
53. Fritsche M., Haessler C,., Brandner G. Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents. Oncogene, 1993, 8, 307-318.
54. Fu L., Minden M.D., Benchimol S. Translational regulation of human p53 gene expression. EMBO, 1996, 15, 4392-4401.
55. Fukasawa K, Choi T., Kuriyama R., RulongS., Vande Wounde G.F. Abnormal centrosome amplification in the absence of p53. Science, 1996, v.271, p. 1744-1747.
56. Fukasawa K., Wiener F., Woud G.F.V., Mai S. Genomic instability and apoptosis are frequent in p53 deficient young mice. Oncogene, 1997, 15, 1295-1302.
57. Funk W.D.,Pak D.T., Karas R.H., Wright W.E., Shay J. W. A transcriptionally active DNA-binding site from human p53 protein complexes. Mol. and Cell. Biol., 1992, 12, 28662871.
58. Gabrielli B.G., Clark J.M., McCormack A.K., Ellem K.A.O. Ultraviolet light-induced G2 phase cell cycle checkpoint blocks cdc25-dependent progression into mitosis. Oncogene, 1997, 15, 749-758.
59. Galaktionov K., Lee A.K., Eckstein E., Draetta G., Mecklet J., Loda M., Beach D. CDC25 phosphatases as potential human oncogenes. Science, 1995, 269, 1575-1577.
60. Garkavtsev I., Kazakov A., Gudcov A., Riabowol K. Supression of the novel growth inhibitor p33INGl promotes neoplastic transformation. Nature Genet., 1996, 14, 415420.
61. Garkavtsev I., Grigorian I.A., Ossovskaya V.S., Chernov M.V., Chumakov P.M., Gudcov
62. A. V. The candidate tumor supressor p33INGl cooperates with p53 in cell growth control. Nature, 1998, 391, 295-298.
63. German J. Chromosome mutation and neoplasia New York, Liss, 1983.
64. Giaccia A.J., KastanM.B. The complexity of p53 modulation: emerging patterns from divergent signals. Genes & Development, 1998, 12, 2973-2983.
65. Ginsberg, I)., Oren, M., Yaniv, M. and Piette J. Protein-binding elements in the promoter region of the mouse p53 gene. Oncogene, 1990, 5, 1285-1290.
66. Gottlieb E., Haffner R., von RudenT., Wagner E.F., OrenM. Down-regulation of wild-type p53 activity interferes with apoptosis of IL-3-dependent hematopoietic cells following IL-3 withdrawal. EMBO J., 1994, 13, 1368-1374.
67. Gottlieb T.M. and Oren M. p53 in growth control and neoplasia. Biochim. Biophys. Acta, 1996,1287,77-102.
68. Graeber T.g., Osmanian C., Jacks T., Housman D.E., Koch C.J., Lowe S.W., Giaccia A.J. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumors. Nature, 1996, 379, 88-91.
69. Grana, X, and E. P. Reddy. Cell cycle control in mammalian cells: role of cyclins, cyclin-dependent kinases (cdks), growth supressor genes and cyclin-dependent kinase (CKIs). Oncogene, 1995, 11,2-11
70. Grand R.J.A. and Owen D. The biochemistry of ras p21. Biochem. J., 1991, 279, 609-631.
71. Greenblatt M.S., Bennet W.P., Hollstein M., Harris C.C. Mutations in p53 tumor suppressor gene due to cancer etiology and molecular pathogenesis. Cancer Res., 1994, v.54, p.4855-4878.
72. Haines, D.S., Landers, J.E., Engle, L.J., and George, D.L. Physical and functional interaction between wild-typi p53 and mdm2 proteins. Mol.Cell Biol., 1994, 14, 11711178.
73. Halazonetis T.D., Davis L.J., Kandil A.N. Wild-type p53 adopts a "mutant"-like conformation when bound to DNA. EMBO J., 1993, 12, 1021-1028.
74. Hall P.A., Kearsey J.M., Coates P.J., Norman D.G., Warbrick E., Cox L.S. Characterisation of the interaction between PCNA and Gadd45. Oncogene, 1995, v. 10, p.2427-2433.
75. Harper J.W., Adami G.R., Wei N., Keyomarsi K, Elledge S.J. The p21 Cdk-interacting protein Cipl is a potent inhibitor of G1 cyclin-dependent kinases. Cell, 1993, 75, 805816.
76. Harvey M., Sands A.T., Weiss R.S., Hegi M.E., Wiseman R.W., Pantazis P., Giovanella B.C., Tainsky M.A., Bradley A., Donehower LA. In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene, 1993, 8, 2457-2467.
77. Haubruck H. and McCormic F. Ras p21: effects and regulation. Biochim. Biophys. Acta, 1991, 1072, 215-229.
78. Haupt Y., Rowan S., Oren M. p53-mediated apoptosis in HeLa cells can be overcome by excess pRb. Oncogene, 1995, 10, 1563-1571.
79. Havre P.A., Yuan J., Hedrick L., Cho K.R., Glazer P.M. p53 inactivation by HPV16 results in increased mutagenesis in human cells. Cancer Res., 1995, 55, 4420-4424.
80. Hawkins P.T., Eguinoa A., Qiu R.G., Stokoe D., Cooke F.T., Walters R., Wennstrom S., Claesson W.L., Evans T., Symons M. PDGF stimulates an increase in GTP-Rac via activation of phosphoinositide 3-kinase. Curr. Biol., 1995, 5, 393-403.
81. He Z, Brinton B.T., Greenblatt J., Hassell J.A., Ingels C.J. The transactivator proteins VP16 and GAL4 bind replication factor A. Cell, 1993, 73, 1223-1232.
82. Hecker D., Page G., Lohrum M., Weiland S., Scheidtmann K.H Complex regulation of the DNA-binding activity of p53 by phosphorylation sites on the interaction with different binding motifs. Oncogene, 1996, 12, 953-961.
83. Helin K. Regulation of cell proliferation by the E2F transcription factors. Curr. Opin. Genet. Dev., 1998, 8, 28-35.
84. Hermeking H. and Eick D. Mediation of c-Myc-induced apoptosis by p53. Science, 1994, 265, 2091-2093.
85. Hirakawa T. and Ruley H.E. Rescue of cells from ras oncogene-induced growth arrest by a second complementing oncogene. Proc. Natl. Acad. Sci. USA, 1988, 85, 1519-1523.
86. Hirano Y., Yaniato K., Tsuchida N. A temperature sensitive mutant of the human p53, Vall38, arrests rat cell growth without induced expression of cipl/wafl/sdil after temperature shift-down. Oncogene, 1995, 10, 1879-1885.
87. Hockenbery D.M., Oltvai Z.N., Yin X.M., Milliman C.L., Korsmeyer S.J. Bcl-2 function in an antioxidant pathway to prevent apoptosis. Cell, 1993, 75, 241-251.
88. Hofer F., Fields S., Schneider C., Martin G.S. Activated Ras interacts with the Ral guanine nucleotide dissciation stimulator. Proc. Natl. Acad. Sci. USA, 1994, 91, 11089-11093.
89. Hollstein M., MetcalfR.A., Welsh J., Montesano R., Harris C.C. Frequent mutation of the p53 gene in human esophageal cancer. Proc. Natl. Acad. Sci. USA, 1990, 87, 9958-9961.
90. Hollstein M., Sidransky D., Vogelstein B., Harris C.C. p53 Mutations in human cancers. Science, 1991, v.253, p.49 53.
91. Hollstein M., Rice K., Greenblatt M.S., Soussi T., Fuchs R., Sorlie T., Hovig E., Smith-Sorensen B., Montesano R., Harris C.C. Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res., 1994, v.22, p.3551 3555.
92. Huang L.-C., Clarkin K.C., Wahl G.M. Senssitivity and selectivity of the DNA damage sensor responsible for activating p53-dependent G1 arrest. Proc. Natl. Acad. Sci. USA, 1996, 93,4827-4832.
93. Hudson J.M., Frade R., Bar-Eli M. Wild-type p53 regulates its own transcription in a celltype specific manner. DNA Cell Biol., 1995, 14, 759-766.
94. Hupp T.R., Meek D. W, Midgley C.A., Lane D.P. Regulation of the specific DNA binding function of p53. Cell, 1992, 71, 875-886.
95. Jacks T. and Weinberg R.A. Cell-cycle control and its watchman. Nature, 1996, 381, 643644.
96. Jackson P., Bos E., Braithwaite A.W. Wild-type p53 down-regulates transcription from different virus enhancer/promoters. Oncogene, 1993, 8, 589-597.
97. Jeffrey P.D., Gorina S., Pavletich N.P. Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms. Science, 1995, 267, 1498-1502.
98. Johnson P., Chung S., Benchimol S. Growth suppression of Friend virus-transformed erythroleukemia cells by p53 protein is accompained by hemoglobin production and is sensitive to erythropoetin. Mol. Cell Biol., 1993, 13, 1456-1463.
99. Johnson, C.R., Morin, P.E., Arrowsmith, C.H., and Freire, -E. Thermodynamic analysis of the structural stability of the tetrameric oligomerization domain of p53 tumor suppressor. Biochemistry, 1995, 34, 5309-5316.
100. Joneson T., McDonough M., Bar-Sagi D., Aelst L.V. RAC regulation of actin polymerization and proliferation by a pathway distinct from Jun kinase. Science, 1996, 274, 1374-1376.
101. Jost C.A., Marin M.C., Kaelin Jr W.G. p73 is a human p53-related protein that can induce apoptosis. Nature, 1997, 389, 191-194.
102. Kaghad M. et al. Monoallelically expressed gene related to p53 at the neuroblastoma supressor-1 locus. Cell, 1997.
103. Kamijo T., Weber J.D., Zambetti G., Zindy F., Roussel M.F, Sherr C.J. Functional and physical interactions of the ARF tumor supressor with p53 and Mdm2. Proc. Natl. Acad. Sci. USA, 1998, 95, 8292-8297.
104. Kastan M.B., Onyekwere O., Sidransky D., Vogelstein B., Craig R.W. Participation of p53 protein in the cellular response to DNA damage. Cancer. Res., 1991, 51, 6304-6311.
105. Kastan M.B., Zhan Q., El-Deiry W.S., Carrier T., Jacks W.V., Walsh B.S., Plunkett B., Vogelstein B., Fornace A.J. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell, 1992, 71, 587-597.
106. Kelman Z. PCNA: structure, functions and interactions. Oncogene, 1997, 14, 629-640.
107. Khan S.H., Wahl G.M. p53 and pRb prevent rereplication in response to microtubule inhibitors by mediating a reversible G1 arrest. Cancer Res., 1998, 58, 396-401.
108. KinzlerA. and Vogelstein B. Gateceepers and caretakers. Nature, 1997, 386, 761-762.
109. Knippschild U., Oren M., Depprt W. Abrogation of wild-type p53 mediated growth-inhibition by nuclear exclusion. Oncogene, 1996, 12, 1755-1765.
110. Ko L.G. andPrives C. p53: puzzle and paradigm. Genes Dev., 1996, 10, 1054-1072.
111. Kremenetskaya O.S., Logacheva N.L, Baryshnikov A.Y., Chumakov P.M., Kopnin B.P. Distinct effects of various p53 mutants on differentiation and viability of human K562 leukemia cells. Oncol Res., 1997, 9, 155-166.
112. R. and Botcham M.R. The acidic transcriptional activation domains of VP 16 and p53 bind the cellular replication protein A and stimulate in vitro BPV-1 DNA replication. Cell, 1993, 73, 1207-1221.
113. R., Waga S., Hannon G.L., Beach D., Stillman B. Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair. Nature, 1994, 371, 534-537.
114. Machelsky L.M. and Hall A. Rho: a connection between receptor signalling and the cytoskeleton. Cell Biol., 1996, 6, 304-310.
115. Maltzman W. and Czyzyk L. UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol. Cell Biol., 1984,4, 1689-1694.
116. Marks, J.R., Davidoff, A.M., Kerns, B.J., Humphrey, P.A., Pence, J.C., Dodge, R.K., Clarke Pearson, D.L., Iglehart, J.D., Bast, R.C.,Jr., and Berchuck, A. Overexpression and mutation of p53 in epithelial ovarian cancer. Cancer Res. 51:2979-2984, 1991.
117. Marshall C.J. Specificity of receptor tyrosine kinase signalling: transient versus sustained extracellular signal-regulated kinase activation. Cell, 1995, 80, 179-185.
118. Marshall C.J. Ras effectors. C.urr. Opin. Cell Biol., 1996, 8, 197-204.
119. Martinez J., Georgoff L, Martinez J., Levine A.J. Cellular localization and cell cycle regulation by a temperature-sensitive p53 protein. Gen. Development, 1991, 5, 151-159.
120. MasudaH., Miller C., Koefer H.P., BattiforaH., ClineM.J. Rearrangement of the p53 gene in human osteogenic sarcomas. Proc. Natl. Acad. Sci. USA, 1987, 84, 7716-7719.
121. Matlashevski G., Lamb P., Pirn D., Peacock J., Crawford L., Benchimol S. Isolation and characterization of a human p53 cDNA clone: expression of the human p53 gene. EMBO, 1984, 3, 3257-3262.
122. Matsuoka S., Huang M, Elledge S. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science, 1998, 282,1893-1897 ■
123. McKay I.A., Marshall C.J., C.ales C., Hall A. Transformation and stimulation of DNA synthesis in NIH-3T3 cells are a titratable function of normal p21N ras expression. EMBO J., 1986, v.5, p.2617-2621.
124. McGrath J.P., Capon D.J., Smith D.H. Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene. Nature, 1983, 304, 501-506.
125. Medema RH, Klompmaker R, Smits VAJ and Rijksen G. p21wafl can block cells at two points in the cell cycle, but does not interfere with processive DNA-replication or stress-activated kinases. Oncogene, 1998,16, 431-441.
126. MeekD. Post-translational modification of p53. Semin. Cancer Biol., 1994, 5, 203-210.
127. Mekeel K.L., Tang W., Kachnic L.A., Luo C-M., DeFrank J.S., Powel S.N. Inactivation of p53 results in high rates of homologous recombination. Oncogene, 1997, 14, 1847-1857.
128. Mercer W. E., Shields M.T., Amin M., Sauve G.J., Appella E., Romano J.W., Ullrich S.J. Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild-type p53. Proc. Natl. Acad. Sci. USA, 1990, 87, 6166-6170.
129. MerrittA., Allen T., Potten C., Hickman J. Apoptosis in small intestinal epithelia from p53-null mice: evidence for a delayed, p53-idependent G2/M-associated cell daeth after y-irradiation. Oncogene, 1997, 14, 2759-2766.
130. Miller S.D., Farmer G., Prives C. p53 inhibits DNA replication in vitro in a DNA-binding-dependent manner. Mol. Cell Biol., 1995, 15, 6554-6560.
131. Milne D.M., Campbell D.G., Caudwell F.B., Meek D.W. Phosphorylation of the tumor suppressor protein p53 by mitogen-activated protein kinases. J. Biol Chem., 1994, 269, 9253-9260.
132. Milne D.M., Campbell L.E., Campbell D.G., MeekD. W. p53 is a phosphorylated in vitro by an ultraviolet radiation-induced protein kinase characteristic of the c-jun kinase, JNK1.,/. Biol Chem., 1995, 270, 5511-5518.
133. Mittnacht S. Control of pRb phosphorylation. Current Opinion in Genetics & Development, 1998, 8, 21-27.
134. Miyashita T., Harigai M., HanadaM., Reed J. C. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res., 1994a, 54, 3131-3135.
135. Morgan D.O. Principles of cdk regulation. Nature, 1995, 374, 131-134.
136. Morgan D.O. Cyclin-dependent kinases: engines, clocks and microprocessors. Annu.Rev.CellDev. Biol., 1997, 13,261-291.
137. Murakami H. and Okayama H. Cell cycle checkpoint kontrol. Experimental and Molecular Medicin, 1997,29, 1-11.
138. Murray A. W. The genetics of cell cycle checkpoints. Curr. Opin. Genet. Dev., 1995, v. 5, 511.
139. Naumovski L. and Cleary M.L. The p53-binding protein 53BP2 also interacts with Bcl2 and impedes cell cycle progression at G2/M. Mol. Cell Biol, 1996, 16, 3884-3892.
140. Nelson W.G. and Kastan M.B. DNA srtand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Moll Cell Biol., 1994, 14, 1815-1823.
141. Newcomb E.W. p53 gene mutation in lymphoid disease and their possible relevance to drug resistance. Leuk. Lymphoma, 1995, 17, 211-221.
142. Niewolik D., Vojtesek B., Kovaric J. p53 derived from human tumour cell lines and containing distinct point mutations can be activated to bind its consensus target sequence. Oncogene, 1995, 10, 881-890.
143. Nikiforov M.A., Hagen K., Ossovskaya V.S., Connor T.M.F., Lowe S., Deichman G.I., Gudkov A.V. p53 modulation of anchorage independent growth and experimental metastasis. Oncogene, 1996, 13, 1709-1719.
144. Notterman D., Young S., Wainger B., Levine A.J. Prevention of mammalian DNA reduplication, following the release from the mitotic spindle checkpoint, requires p53 protein, but not p53-mediated transcriptiona! activity. Oncogene, 1998, 17, 2743-2751.
145. Oltvai Z.N., Milliman C.L., Korsmeyer S.J. Bcl-2 heterodimerizes in vivo with a coserved homolog, Bax, that accelerates programmed cell death. Cell, 1993, 74, 609-619.
146. Ouchi T., Monteiro A.N.A., August A., Aaronson S.A., Hanafusa H. BRCA1 regulates p53-dependentgene expression. Proc.Natl.Acad. Sci.USA, 1998, 95, 2302-2306.
147. Ozkinay C., Mitelman F. A simple trypsin-Giemsa technique producing simultaneous G-and C-banding in human chromosomes. Hereditas, 1979, v.90, p. 1-4.
148. Parada L.F., Land H., Weinberg R.A., Wolf D., Rotter D. Cooperation between gene encoding p53 tumor antigen and ras in cellular transformation. Nature, 1984, v.312, p.649 651.
149. Park D.J., Nakamura H., Chumakov A.M., .Said J.N., Miller C.W., Chen D.L., Koeffler H.P. Transactivational and DNA binding abilities of endogenous p53 in p53 mutant cell lines. Oncogene, 1994, 9, 1899-1906.
150. Pavletich N.P., Chambers K.A., Pabo C.O. The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots. Genes Dev., 1993, 7, 25562564.
151. PaulovichA., Toczyski D., Hartwell. When cechkpoints fail. Cell, 1997,88, 315-321
152. Peng C.-Y., Graves P. R, Thoma R.S., WuZ., Shaw A.S., Piwnica-Worms H. Mitotic and G2 checkpoint control: regulatio of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science, 1997, 277, 1501-1505.
153. Perry M.E., Piette J., Zawadzki J. A., Harvey D., Levine A J. The mdm-2 gene is induced in response to UV light in a p53-dependent manner. Proc. Natl. Acad. Sci., 1993, 90, 11623-11627.
154. Peeper D.S., Upton T.M., Ladha M.H., NeumanE., Zalvide J., Bernards r., DeC.aprio J.A., Ewen M.E. Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein. Nature, 1997, 386, 177-181.
155. Pocard M, Chevillard S., Villaudy J., Poupon M.F., Dutrillaux B., Remvikos Y. Different p53 mutations produce distinct effects on the ability of colon carcinoma cells to become blocked at the Gl/S boundary after irradiation. Oncogene, 1996, 12, 875-882.
156. Polyak K., Xia Y, Zweier J.L., Kinzler K.W., Vogelstein B. A model for "p53-induced apoptosis. Nature, 1997, v.389, p.300-305.
157. Powell S.N., DeFrank J.S., Cornell P., Eogan M., Preffer F., Dombkowski D., Tang W., Friend S. Differential sensitivity of p53(-) and p53(+) cells to caffeine-induced radio sensitization and override of G2 delay. Cancer Res., 1995, v.55, p. 1643-1648.
158. Prives C. and Manfredi I.J. The p53 tumour suppressor protein: meeting review. Genes Dev., 1993, 7, 529-534.
159. Prives C. How loops, (3 sheets, and a helices help us to understand p53. Cell, 1994, 78, 543-546.
160. Prives C. Signaling to p53: Breaking the MDM2-p53 Circuit. Cell, 1998, 95, 5-8.1.l
161. Purdie C.A., Harrison D.J., Peter A., Dobbie L., White S., Howie S.EM., Salter D.M., Bird C.C., Wyllie A.H., Hooper M.L., Clarke A.R. Tumour incidence, spectrum and ploidy in mice with a large deletion in the p53 gene. Oncogene, 1994, 9, 603-609.
162. Qiu R.-G., Chen J., Kirn D., McCormick F., Symons M. An essential role for Rac in Ras transformation. Nature, 1995, 374, 457-459.
163. Raycroft L., Wu H., Lozano G. Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. Science, 1990, 249, 1049-1051.
164. Reddy E.P., Reynolds R.K., Santos E., Barbacid M. A pointmutation is responsible for the acquisition of transforming propeties by the T24 human bladder carcinoma oncogene. Nature, 1982, 300, 149-152.
165. Reed M., Woelker B., Wang P., Wang Y., Anderson M.E., Tegtmeyer P. The C-terminal domain of p53 recognizes DNA damaged by ionizing radiation. Proc. Natl. Acad. Sci., 1995, 92, 9455-9459.
166. Rudner A.D. and Murray A. W. The spindle assembly checkpoint. Current Opinion in cell Biology, 1996, 8, 773-780.
167. Ruley H.E. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature, 1983, 304, 602-606.
168. Ruley H.E. Transforming collaborations between ras and nuclear oncogenes. Cancer Cells, 1990, 2, 258-268.
169. Rüssel K.J., Wiens L.W., Demers G.W., Galloway DA., Plön S.E., Grudine M. Abrogation of the G2 checkpoint-deficient and Gl checkpoint-competent cells. Cancer Res., 1995, v.55, p.1639-1642.
170. Ryan J.J., Danish R., Gottlieb C.A., Clarke M.F. Cell cycle analysis of p53 induced cell death in murine erythroleukemia cells. Mol. Cell Biol., 1993, 13, 711-719.
171. Sablina A.A., Ilyinskaya G. V., Rubtsova S.N., Agapova L.S., Chumakov P.M., Kopnin B.P. Activation of p53 mediated cell cycle checkpoint in response to micronuclei formation. J. Cell Sei., 1998.
172. Sakaguchi K, Herrera J., Saito S., Miki T., Bustin M., Vassilev A., Anderson C., Apella E. DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes & Development, 1998, 12, 2831-2841.
173. Sakamuro d., Sabbatini P., White E., Prendergast G.C. The polyproline region of 53 is required to activate apoptosis but not growth arrest. Oncogene, 1997, 15, 887-898.
174. Sands A.T., Suraokar M.B., Sancher A., Marth J.E., Donehower L.A., Bradley A. p53 deficiency does not affect the accumulation of point mutations in a transgene target. Proc. Natl. Acad. Sei., 1995, 92, 8517-8521.
175. Satoh T., Endo M., Nakafuku M., Akiyama T., Yamamoto T., Kaziro Y. Accumulation of p21ras.GTP in response to stimulation with epidermal growth factor and oncogene products with tyrosine kinase activity. Proc. Natl. Acad. Sei., 1990, 87, 7926-7929.
176. Satoh T., Endo M., Nakafuku M., Nakamura S., Kaziro Y. Plateled-derived growth factor stimulates formation of active p21ras.GTP complex in Swiss mouse 3T3 cells. 'Proc. Natl. Acad. Sei., 1990, 87, 5993-5997.
177. Serrano M., Gomez-Lahoz E., DePinho R.A., Beach /)., Bar-Sagi D. Inhibition of ras-induced proliferation and cellular transformation by pl6/INK4. Science, 1995, 267, 249252.
178. Serrano M., Lee H.-W., Chin L., Cordon-Cardi C., Beach D., DePinho R.A. Role of the INK4a locus in tumor suppression and cell mortality. Cell, 1996, 85, 27-37.
179. Serrano M., Lin A.W., McCurrach M.E., Beach D., Lowe S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and pl6/inkl4a. Cell, 1997, 88, 593-602.
180. Shapiro G.I., Edwards C.D., EwenM.E., Rollins B.J. pl6INK4a participates in a G1 arrest checkpoint in response to DNA damage. Mol.Cell. Biol., 1998, 18, 378-387.
181. SharanS., Morimatsu M., Albrecht U., Lim D., Re gel E., Dinh C., Sands A., Eichele G., Hasty P., Bradley A. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature, 1997, 386, 804-810.
182. Shaulsky G., Goldfinger N., Tosky M.S., Levine A.J., Rotter V. Nuclear localization is essential for the activity of p53 protein. Oncogene, 1991, 6, 2055-2065.
183. Shaulian E., Zauberman A., Ginsberg D., OrenM. Identification of a minimal transforming domain of p53: negative dominance through abrogation of sequence-specific DNA binding. Mol. Cell Biol., 1992, 12, 5581-5592.
184. Shaulian E., Resnitzky D., Shifman O., Blandino G., Amsterdam A., Yayon A., Oren M. Induction of Mdm2 and enhancement of cell survival by bFGF. Oncogene, 1997, 15, 2717-2725.
185. Shaw P., Tardy S., Benito E., Obrador A., Costa G. Occurrence of Ki-ras and p53 mutations in primary colorectal tumors. Oncogene, 1991, v.6, p.2121-2128.
186. Sheikh M.S., Chen Y.Q., Smith M.L., Fornace A.J.Jr. Role of P21Wafl/ciP1/sdil in cell death and DNA repair as studied using a tetracycline-inducible system in p53-deficient cells. Oncogene, 14, 1875-1882.
187. Shefner M., Werness B., Huibregtse J., Levine A., Howley P. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell, 1991, 63, 1129-1136.
188. Sheikh M.S., Chen Y.Q., Smith M.L., Fornace A.J Jr. Role of P21Wafl/ciP!/sdil in cell death and DNA repair as studied using a tetracycline-inducible system in p53-deficient cells. Oncogene, 1998, .14, 1875-1882.
189. Sherr C.J. and Roberts J.M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev., 1995,9, 1149-1163.
190. Sherr C.J. Cancer cell cycles. Science, 1996, 274, 1672-1677.
191. Sherr C.J. Tumor surveillance via the ARF-p53 pathway. Genes & Development, 1998, 12, 2984-2991.
192. Shigesada K, Stark G.R., Maley J.A., Niswander L.A., Davidson J.N. Construction of a cDNA to the hamster CAD gene and its application toward defining the domain for aspartate transcarbamilase. Mol. Cell Biol., 1985,5, 1735-1742.
193. Shin K-H. Tannyhill R.J., Liu X., Park N-H. Oncogenic transformation of HPV-immortalized human oral keratinocytes is associated with the genetic instability of cells. Oncogene, 1996, 12, 1089-1096.
194. Shivji M.K.K., Kenny M.K., Wood R.D. Proliferating cell nuclear antigen is required for DNA excision repair. Cell, 1992, 69, 367-374.
195. Smith M.R., DeGubicus S.J., Stacey D.W. Requirement for c-ras proteins during viral oncogene transformation. Nature, 1986, 320, 540-543.
196. Smith M.L., Chenl.-T., Zhan Q., Bae I., ChenC.-Y., Gilmer T.M., KastanM.B., O'Connor P.M., Fornace A.J. Interaction of the p53-regulsted protein Gadd45 with proliferating cell nuclear antigen. Science, 1994, 266, 1376-1380.
197. Smith M.L., Chen I.T., Zhan Q., O'Connor P.M., Fornace A.J.J. Involvement of the p53 tumor suppressor in repair of u.v.-type DNA damage. Oncogene, 1995, v. 10, p. 10531059.
198. Soddu S., Blandino G., Scardigli R., Martinelli R., Rizzo M.G., Crescenzi M., Sacchi A. Wild-type p53 induces diverse effect in 32D cells expressing different oncogenes. Mol. Cell Biol., 1996, 16, 487-495.
199. Soussi T., Caron de Formental C., Mechali M., May P., Kress M. Cloning and characterization of a cDNA from Xenopus laevis coding for a protein homologous to human and murine p53. Oncogene, 1987, v.l, p.71 78.
200. Soussi T., Caron de Formental C., May P. Structural aspects of the p53 protein in relation to gene evolution. Oncogene, 1990, 5, 945-952.
201. Soussi T, Legros Y., Lubin R., Ory K, Schlichtholz B. Multifactorial analysis of p53 alteration in human cancer: a review. Int.J.Cancer, 1994, 57, 1-9.
202. Srinivasan, R., Roth, J.A., and Maxwell, S.A. Sequence-specific interaction of a conformational domain of p53 with DNA. Cancer Res., 1993, 53,5361-5364.
203. Stark G.R. Regulation and mechanisms of mammalian gene amplification. Adv. Cancer Res., 1993, v.61,p.87-113.
204. Stewart N, Hicks GG, Paraskevas F and Mowat M. Evidence for a second cell cycle block at G2/M by p53. Oncogene, 1995, 10, 109-115.
205. Stenger J.E., Mayr G.A., Mann K., Tegtmeyer P. Formation of stable p53 homotetramers and multiples oftetramers. Mol. Carcinogen., 1992, 5, 102-106.
206. Stokoe D., Macdonald S.G., Cadwallader K., Symons M., Hancock J.F. Activation of Ras as a result of recruitment to the plasma membrane. Science, 1994, 264, 1463-1467.
207. Strauss, B.E., Shivakumar, C., Deb, S.P., Deb, S., and Haas, M. The MDR1 downstream promoter contains sequence-specific binding sites for wild-type p53. Biochem.Biophys.Res.Commun. 217:825-831, 1995.
208. Stromskaya T.P., Grigorian I.A., Ossovskaya V.S., Rybalkina E.Y., Chumakov P.M., Kopnin B.P. Cell specific effects of ras oncogene and proteine kinase C agonist TPA on P-glycoprotein function. FEBSLett., 1995, 368, 373-376.
209. Sturzbecher H.-W., Donzelmann B., Henning W., Knippchild U., Buchhop S. p53 is linked directly to homologous recombination processes via RAD51/RecA protein interaction. EMBO, 1996, 15, 1992-2002.
210. Sun H., Tonks N.K., Bar-Sagi D. Inhibition of Ras-induced DNA synthesis by expression of the phosphatase MKP-1. Science, 1994, 266, 285-288.
211. SunX.-F., Johannsson O., Hakansson S., SellbergG., Nordenskjold B., OlssonH., BorgA. A novel p53 germline alteration identified in a late onset breast cancer kindred. Oncogene, 1996, 13, 407-411.
212. Sun Y., Bian J., Wang Y., Jacobs C. Activation of p53 transcriptional activity by 1,10-phenanthroline, a metal chelator and redox sensitive compaund. Oncogene, 1997, 14, 385-393.
213. Takenaka I., Morin F., Seizinger B.R., Kley N. Regulation of the sequence-specific DNA binding function of p53 by protein kinase C and protein phosphatases. J. Biol. Chem., 1995,270,5405-5411.
214. Taylor W., Agarwal M., Agarwal A., Stacey JX, Stark G. p53 inhibits entery into mitosis whin DNA synthesis is blocked. Oncogene, 1998, 18,283-295.
215. Thut C., Chen J.L., Klemm R., Tjian R. p53 transcriptional activation mediated by coactivators TAFII40 and TAFII60. Science, 1995, 267, 100-104.
216. Thut C.J., Goodrich J.A., Tjian R. Repression of p53-mediated transcription by MDM2: a dual mechanism. Genes Dev., 1997, 11, 1974-1986.
217. Tishler, R.B., Calderwood, S.K., Coleman, C.N., and Price, B.D. Increases in sequence specific DNA binding by p53 following treatment with chemotherapeutic and DNA damaging agents. Cancer Res., 1993, 53, 2212-2216.
218. Traverse S., Cohen P., Paterson H., Marshall C.J., Rapp U., Grand R.J.A. Specific assotiation of activated MAP kinase kinase kinase (Raf) with the plasma membranes of ras-transformed retinal cells. Oncogene, 1993, 8, 3175-3181.
219. Tsang N.-M., Nagasawa H., Li C., Little J. Abrogation of p53 function by transfection of HPV16 E6 gene enhances the resistance of human diploid fibroblasts to ionizing radiation. Oncogene, 1995, 10, 2403-2408.
220. Van den Heuvel S. and Harlow E. Distinct role for cycline-dependent kinases in cell cycle control. Science, 1993, 262, 2050-2054.
221. Vogel U.S., Dixon R.A.F., Schaber M.D., Diehl R.E., Marshall M.S., Scolnick E.M., Srgal IS., Gibbs J.B. Cloning of bovine GAP and its interaction with oncogenic ras p21. Nature (.Lond.), 1988, 335, 90-93.
222. Vogelstein B., Kinzler K. W. p53 function and disfunction. Cell, 1992, 70, 523-526.
223. Vogelstein, B. and Kinzler, K.W. Tumour-suppressor genes. X-rays strike p53 again news; comment. Nature, 1994, 370, 174-175.
224. Waga S., Hannon G.J., Beach D., Stillman B. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature, 1994, 369,574-578.
225. Wagner A.J., Kokontis J.M., Hay. Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and ability of p53 to induce p21/wafl/cipl. Genes Dev., 1994,8,2817-2830.
226. Waldman T, Lengauer C, Kinzler K and Vogelstein B. Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature, 1996, 381, 713-716.
227. Walker K.K. and Levine A.J. Identification of a novel p53 functional domain wich is necessary for efficient growth suppression. Proc. Natl. Acad. Sci. USA, 1996, 93, 1533515340.
228. Wang Y, Reed M., Wang P., Stenger J.E., Mayr G.,Anderson M.E., Schwedes J.F., Tegtmeyer P. p53 domains: identification and cherecterization of two autonomous DNA-binding regions. Genes & Development, 1993, 7, 2575-2586.
229. Wang Y. and Prives C. Increased and altered DNA binding of human p53 by S and G2/M but not G1 cyclin-dependent kinase. Natnre, 1995, 376, 88-91.
230. Wang H.-G., Rapp U.R., Reed J.C. Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell, 1996, 87, 629-638.
231. Wang X., Zhan Q., Coursen J., Khan A., Kontny H., Yu L., Hollander M., O'Connor P., Fornace A., Harris C. GADD45 induction of G2/M cell cycle checpoint. PNAS, 1999, 96, 3706-3711.
232. Wartmann M., Davis R.J. The native structure of the activated raf protein kinase is a membrane-bound multi-subunit complex. J. Biol., C.hem., 1994, 269, 6695-6701.
233. Waterman J.L., Shenk J.L., Halazonetis T.D. The dihedral symmetry of the p53 tetramerization domain mandates a conformational switch upon DNA binding. EMBO J., 1995,14,512-519.
234. Weinberg R.A. Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res., 1989, 49, 3713-3721.
235. WeintraubH., Hauschka S., Tapscott S.J. The MCK enhancer contains a p53 responsive element. Proc. Natl. Acad. Sci. USA, 1991, 88, 4570-4571.
236. Wennstrom S., Hawkins P., Cooke F., Hara K, Yonezawa K, Kasuda M., Jackson T., Claesson W.L., Stephens L. Activation of phosphoinositide 3-kinase is required for PDGF-stimulated membrane ruffling. Curr. Biol., 1994, 4, 385-393.
237. Werness B.A., Levine A. J., Howlay P.M. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science (Washington DC), 1990, 248, 76-79.
238. White A.E., Livanos E.M., Tlsty T.D. Differential disruption of genomic integrity and cell cycle regulation in human fibroblasts by the HPV oncoproteins. Genes. Dev., 1994, v.8, p.667-677.
239. White E. Life, death, and the pursuit of apoptosis. Genes Dev., 1996, 10, 1-15.
240. Williams B.O., Remington L., Albert D.M., Mukai S., Bronson R.T., Jacks T. Cooperative tumorigenic effects of germline mutations in Rb and p53. Nature Genet., 1994, 7, 480484.
241. Winston J.T., Coats S.R., Wang Y.-Z., Pledger W.J. Regulation of the cell cycle machinery by oncogenic Ras. Oncogene, 1996, 12, 127-134.
242. Whitehead R.H., Macrae F.A., St. John D.J.B., Ma J. A colon cancer cell line (LIM1215) derived from a patient with inherited nonpolyposis colorectal cancer. J. Natl. Cancer Inst., 1985, 74, 759-765.
243. Wright E.C., Goldgar D.E., Fain P.R. A genetic map of human chromosome 17p. Genomics, 1990, 7, 103-109.
244. Wyllie, F.S., Haughton, M.F., Blaydes, J.P., Schlumberger, M., and Wynford-Thomas, D. Evasion of p53-mediated growth control occurs by three alternative mechanisms in transformed thyroid epithelial cells. Oncogene 10:49-59; 1995.
245. Wyllie A. Clues in the p53 murder mystery. Nature, 1997, v.389, p.237-238.
246. Wu X., Bayle J.H., Olson D., Levine A.J. The p53-mdm-2 autoregulatory feedback loop. Genes&Development, 1993, 7, 1126-1132.
247. Wu H. and Lozano G. NF-kappa B activation of p53. A potential mechanism for suppressing cell growth in response to stress. J.Biol.Chem., 1994, 269, 20067-20074.
248. Wu X. and Levine A.J. p53 and E2F-1 cooperate to mediate apoptosis. Proc. Natl. Acad. ScL, U.S.A., 1994, v.91, p.3602-3606.
249. Xiong Y., Hannon G. J., Zhang H., Casso D., Kobayashi R., Beach D. p21 is a universal inhibitor of cyclin kinases. Nature, 1993, 366, 701-704.
250. Xiong V., Zhang H., Beach D. Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Genes Dev., 1993, 7, 1572-1583.
251. Yamaizumi, M. and Sugano, T. U. v.-induced nuclear accumulation of p53 is evoked through DNA damage of actively transcribed genes independent of the cell cycle. Oncogene 9:2775-2784, 1994.
252. Yew, P.R. and Berk, A.J. Inhibition of p53 transactivation required for transformation by adenovirus early IB protein. Nature, 1992, 357, 82-85.
253. Yew P.R., Liu X., Berk A.J. Adenovirus Elb oncoprotein tethers a transcriptional repression domain to p53. Genes Dev., 1994, 8, 190-202.
254. Yin Y, Tainsky M.A., Bishoff F.Z., Strong L.C., Wahl G.M. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell, 1992, 70, 937-948.
255. Yonish Rouach E., Resnitzky IX, Lote M.J., Sachs L., Kimchi A., Oren M. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature, 1991, 352, 345-347.
256. Yonish-Rouach E., Grunwald /)., Wilder S., Kimchi A., May E., Lawrence J.J., May P., Oren M. p53 mediated cell death: relationship to cell cycle control. Mol. Cell Biol., 1993, 13, 1415-1423.
257. Zaichuk, T.A., N.V.Kuznetsov, V.S.Ossovskaya, B.P.Kopnin, and P.M.Chumakov. Specific DNA-binding properties of p53 oncoprotein from human tumor cell lines. Proc. Russian Acad. Sci., 1993, 330, 386-389.
258. Zambetti G.P., Olson D., Labow M., Levine A.J. A mutant p53 protein is required for maintenance of the transformed phenotype in cells transformed with p53 plus ras cDNAs. Proc. Natl. Acad. Sci. USA, 1992, 89, 3952-3956.
259. Zambetti G.P., Bargonetti J., Walker K, Prives C., Levine A.J. Wild-type p53 mediates positive regulation of gene expression through a specific DNA-sequence element. Genes Dev., 1992, 6, 1143-1152.
260. Zambetti G.P., Levine A.J. A comparison of the biological activities of wild type and mutant p53. FASEB J., 1993, v.7, p.855-865.
261. Zamzami N., Marchetti P., Castedo M., Hirsch 7'., Susin S.A., Masse B., Kroemer G. Inhibitors of permeability transition interfere with the disruption of the mitochondrial transmembrane potentialduring apoptosis. FEBSLett., 1996, 384, 53-57.
262. Zauberman, A., Barak, Y., Ragimov, N., Levy, N., and Oren, M. Sequence-specific DNA binding by p53: identification of target sites and lack of binding to p53 MDM2 complexes. EMBO J., 1993, 12, 2799-2808.