Abstract
Imbalanced activity of the mechanism that controls cell division is a prerequisite for malignant transformation of a normal cell. The present review considers this multi-step mechanism, which is usually called the G1-S checkpoint. Besides, tumor cells are characterized by the presence of telomerase, an enzyme responsible for restoration of chromosome ends after replication and thus providing for unlimited cell division. The main point of the present article is to find out whether the activation of telomerase is controlled by the G1-S checkpoint or does not depend on it. The principal components of the G1-S checkpoint, such as cyclin-dependent kinases, retinoblastoma and E2F proteins, control the activity of telomerase. In their turn they accumulate and transmit signals from various sources inside and outside the cell. Thus, various changes in tumor cells can activate telomerase through the G1-S checkpoint. Such are the suggested effects on telomerase of Myc, p53, Waf1, protein kinases B and C, Wnt5A, TGFβ, WT1, and estrogens. However, Myc, p53, WT1, estrogens, protein kinases B and C, and TGFβ can also directly influence telomerase independently of the G1-S checkpoint mechanism. Moreover, in 30% of human tumors the gene of the key subunit of telomerase (hTERT) is amplified, possibly due to chromosomal rearrangements unassociated with the activity of the G1-S checkpoint. Thus, telomerase seems to be activated not by a single agent but due to combined action of various factors, both with involvement of the G1-S checkpoint mechanism and independently of it.
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REFERENCES
Abott, A. A. (2002) Nature, 416, 470-474.
Kim, N. W., Piatyszek, M. A., Prowse, K. R., and Harley, C. B. (1994) Science, 266, 2011-2015.
Krug, U., Ganser, A., and Koeffler, H. P. (2002) Oncogene, 21, 3475-3495.
Levens, D. (2002) PNAS, 99, 61-71.
Steinman, R. A. (2002) Oncogene, 21, 3403-3413.
Zajac-Kaye, M. (2001) Lung Cancer, 34, S43-S46.
Sidransky, D. (1996) Ann. Rev. Med., 47, 285-301.
Tanappfel, A., and Wittekind, C. (2002) Virchows Arch., 440, 345-352.
Adjei, A. A. (2001) J. Natl. Cancer Inst., 93, 1062-1074.
Agarwal, M. L., Taylor, W. R., Chernov, M. V., Chernova, O. B., and Stark, G. R. (1998) J. Biol. Chem., 273, 1-4.
Kiselev, L. M., Lutsenko, S. V., and Severin, S. E. (2002) Vopr. Biol. Med. Farm. Khim., 3, 3-9.
Coussens, L. M., Fingleton, B., and Matrisian, L. M. (2002) Science, 295, 2387-2392.
Shchelkunov, S. N. (2001) Soros Obrazovat. Zh., 7, 26-30.
Peltomaki, P. (2001) Hum. Mol. Genet., 10, 735-740.
Bortner, C. D., and Cidlowski, J. A. (2002) Ann. Rev. Pharmac. Toxicol., 42, 259-281.
Johnstone, R. W., Ruefli, A. A., and Lowe, S. W. (2002) Cell, 108, 153-164.
Delihas, N. (2001) Curr. Drug Targets, 2, 167-180.
Gross, A. (2001) Life, 52, 231-236.
Evan, G., and Littlewood, T. (1998) Science, 281, 1317-1321.
Olovnikov, A. M. (1971) Dokl. Akad. Nauk SSSR, 201, 1496-1499.
Marx, J. (2002) Science, 295, 2348-2351.
Shay, J. W., Zou, Y., Hiyama, E., and Wright, W. E. (2001) Hum. Mol. Genet., 10, 677-685.
Bryan, T. M., and Cech, T. R. (1999) Curr. Opin. Cell. Biol., 11, 318-324.
Reddel, R. R. (1998) Bioessays, 20, 977-984.
Dandjinou, A. T., Dionne, I., Gravel, S., and LeBel, C. (1999) Histol. Histopathol., 14, 517-524.
Zhang, A., Zheng, C., Lindvall, C., Hou, M., Ekedahl, J., Lewensohn, R., Yan, Z., Yang, X., Henriksson, M., Blennow, E., Nordenskjold, M., Zetterberg, A., Bjorkholm, M., Gruber, A., and Xu, D. (2000) Cancer Res., 60, 6230-6235.
Davis, A. J., and Siu, L. L. (2000) Cancer Invest., 18, 269-277.
Dhaene, K., Marck, E. V., and Parwaresch, A. J. (2000) Virchows Arch., 437, 1-16.
Beattie, T. L., Zhou, W., Robinson, M. O., and Harrington, L. (1998) Curr. Biol., 8, 177-180.
Price, C. M. (1999) Curr. Opin. Genet. Develop., 9, 218-224.
Weinrich, S. L., Pruzan, R., Ma, L., Ouellette, M., Tesmer, V. M., Holt, S. E., Bodnar, A. G., Lichtsteiner, S., Kim, N. W., and Trager, J. B. (1997) Nat. Genet., 17, 498-502.
Forsyth, N. R., Wright, W. E., and Shay, J. W. (2002) Differentiation, 69, 188-197.
Zhao, J.-Q., Glasspool, R. M., and Hoare, S. F. (2000) Neoplasia, 2, 531-539.
Nakamura, T. M., Morin, G. B., Chapman, K. B., Weinrich, S. L., and Andrews, W. H. (1997) Science, 277, 955-959.
Oulton, R., and Harrington, L. (2000) Curr. Opin. Oncol., 12, 74-81.
Feng, J., Funk, W. D., Wang, S. S., Weinrich, S. L., and Avillio, A. A. (1995) Science, 269, 1236-1241.
Yi, X., Tesmer, V. M., Savre-Train, I., Shay, J. W., and Wright, W. E. (1999) Mol. Cell. Biol., 19, 3989-3997.
Oh, S., Song, Y.-H., Kim, U.-J., Yim, J., and Kim, T. K. (1999) Biochem. Biophys. Res. Commun., 263, 361-365.
Oh, S., Song, Y., Yim, J., and Kim, T. K. (1999) J. Biol. Chem., 274, 37473-37478.
Ulaner, G. A., Hu, J.-F., Vu, T. H., Oruganti, H., Giudice, L. C., and Hoffman, A. R. (2000) Int. J. Cancer, 85, 330-335.
Yi, X., White, D. M., Aisner, D. L., Baur, J. A., Wright, W. E., and Shay, J. W. (2000) Neoplasia, 2, 433-440.
Liu, J.-P. (1999) FASEB J., 13, 2091-2104.
Minamino, T., Mitsialis, S. A., and Kourembanas, S. (2001) Mol. Cell. Biol., 21, 3336-3342.
Crowe, D. L., and Nguyen, D. C. (2001) Biochim. Biophys. Acta, 1518, 1-6.
Crowe, D. L., Nguyen, D. C., Tsang, K. J., and Kyo, S. (2001) Nucleic Acids Res., 29, 2789-2794.
Alitalo, K., Koskinen, P., Makela, T. P., Saksela, K., Sistonen, L., and Winquist, R. (1997) Biochim. Biophys. Acta, 907, 1-32.
Greenberg, R. A., O'Hagan, R. C., Deng, H., and Xiao, Q. (1999) Oncogene, 18, 1219-1226.
Horikawa, I., Cable, P. L., Afshari, C., and Barrett, J. C. (1999) Cancer Res., 59, 826-830.
Takakura, M., Kyo, S., Kanaya, T., and Hirano, H. (1999) Cancer Res., 59, 551-557.
Wu, K._J., Grandori, C., Amacker, M., and Simon-Vermot, N. (1999) Nature Genet., 21, 220-224.
Kanaya, T., Kyo, S., Hamada, K., and Takakura, M. (2000) Clin. Cancer Res., 6, 1239-1247.
Kusumoto, M., Ogawa, T., Mizumoto, K., and Ueno, H. (1999) Clin. Cancer Res., 5, 2140-2147.
Xu, D., Wang, Q., Gruber, A., and Bjorkholm, M. (2000) Oncogene, 19, 5123-5133.
Li, H., Cao, Y., Berndt, M. C., Funder, J. W., and Liu, J.-P. (1999) Oncogene, 18, 6785-6794.
Kalassy, M., Martel, N., Damour, O., Yamaskai, H., and Nakazawa, H. (1998) Mol. Carcinog., 21, 26-36.
Helmreich, E. J. M. (2001) The Biochemistry of Cell Signaling, Oxford University Press, Oxford.
Leslie, N. R., and Downes, C. P. (2002) Cell Signaling, 14, 285-295.
Cantley, L. C. (2002) Science, 296, 1655-1657.
Kang, S. S., Kwon, T., Kwon, D. Y., and Do, S. I. (1999) J. Biol. Chem., 274, 1385-1389.
Breitschopf, K., Zeiher, A. M., and Dimmeler, S. (2001) FEBS Lett., 493, 21-25.
Goekjian, P. G., and Jirousek, M. R. (2001) Expert. Opin. Invest. Drugs, 10, 2117-2140.
Newton, A. C. (2001) Chem. Rev., 101, 2353-2364.
Li, H., Zhao, L., Yang, Z., Funder, J. W., and Liu, J.-P. (1998) J. Biol. Chem., 273, 33436-33442.
Bodnar, A. G., Kim, N. W., Effros, R. B., and Chiu, C. P. (1996) Exp. Cell Res., 228, 58-64.
Ku, W.-C., Cheng, A.-J., and Wang, T.-Z. V. (1997) Biochem. Biophys. Res. Commun., 241, 730-736.
Yu, C. C., Lo, S. C., and Wang, T. C. (2001) Biochem. J., 355 (Pt. 2), 459-464.
Moon, R. T., Bowerman, B., Boutros, M., and Perrimon, N. (2002) Science, 296, 1644-1646.
Olson, D. J., Oshimura, M., Otte, A. P., and Kumar, R. (1998) Tumor Biol., 19, 244-252.
Attisano, L., and Wrana, J. L. (2002) Science, 296, 1646-1647.
Orian, A., and Eisenman, N. (2001) Science's STKE: http://stke.sciencemag.org/cgi/content/full/OC-sig-trans;2001/88/pe1.
Seoane, J., Pouponnot, C., Staller, P., Schader, M., Eilers, M., and Massague, J. (2001) Nat. Cell. Biol., 3, 400-408.
Yang, H., Kyo, S., Takatura, M., and Sun, L. (2001) Cell Growth Differentiation, 12, 119-127.
Massague, J., and Weis-Garcia, F. (1996) Cancer Surv., 27, 41-64.
Online Mendelian Inheritance in Man: www.ncbi.nlm.nih.gov/omim/wt1.
Hewitt, S. M., Hamada, S., McDonnell, T. J., Rauscher, F. J., and Saunders, G. F. (1995) Cancer Res., 55, 5386-5389.
Englert, C., Maheswaran, S., Garvin, A. J., Kreidberg, J., and Haber, D. A. (1997) Cancer Res., 57, 1429-1434.
Castro-Rivera, E., Samudio I., and Safe, S. (2001) J. Biol. Chem., 276, 30853-30861.
Planas-Silva, M. D., Donaher, J. L., and Weinberg, R. A. (1998) Cancer Res., 30, 511-524.
Prall, O. W., Rogan, E. M., and Sutherl, R. L. (1998) J. Steroid Biochem. Mol. Biol., 65, 169-174.
Misiti, S., Nanni, S., and Fontemaggi, G. (2000) Mol. Cell. Biol., 20, 3764-3771.
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Altshuler, M.L., Severin, S.E. & Glukhov, A.I. The Tumor Cell and Telomerase. Biochemistry (Moscow) 68, 1275–1283 (2003). https://doi.org/10.1023/B:BIRY.0000011648.51641.04
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DOI: https://doi.org/10.1023/B:BIRY.0000011648.51641.04