Abstract
The human polyomavirus JC virus is the etiologic agent of progressive multifocal leukoenceph-alopathy (PML). As the JC virus early promoter directs cell-specific expression of the viral replication factor large T antigen, transcriptional regulation constitutes a major mechanism of glial tropism in PML. It has been demonstrated that SV40 or JC virus large T antigen interacts with p53 protein and regulates many viral and cellular genes. In this study we found that p53 represses the JC virus early promoter in both glial and nonglial cells. To identify the cis-regula-tory elements responsible for p53-mediated repression, deletional and site-directed mutational analyses were performed. Deletion of the enhancer region diminished p53-mediated transcriptional repression. However, point mutations of several transcription factor binding sites in the basal promoter region did not produce any significant changes. In support of this observation, when the enhancer was fused to a heterologous promoter, p53 reduced the promoter activity about three fold. These results indicate that the enhancer region is important for the repression of JC virus transcription by p53. Furthermore, coexpression of JC virus T antigen with a p53 protein abolished p53-mediated repression of the JC virus early promoter in non-glial cells, but not in glial cells. This finding suggests that T antigen interacts with p53 and regulates JC virus transcription in a cell-specific manner.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Astrom, K. E., Mancall, E. L., and Richardson, E.P., Progressive multifocal leukoencephalopathy.Brain, 81, 93–111 (1958).
Bacellar, H., Munoz, A., Miller, E. N., Cohen, B. A., Besley, D., Selens, O. A., Becker, J. T., and McArther, J. C., Temporal trends in the incidence of HIV-1-related neurological diseases.Neurology, 44, 1892–1900 (1994).
Bargonetti, J., Friedman, P. N., Kern, S. E., Vogelstein, B., and Prives, C., Wild-type but not mutant p53 immunopurified proteins bind to sequences adjacent to the SV40 origin of replication.Cell, 65, 1083–1091 (1991).
Dobbelstein, M. and Roth, J., The large T antigen of simian virus 40 binds and inactivates p53 but not p73.J. Gen. Virol., 79, 3079–3083 (1998).
El-Deiry, W. S., Kern, S. E., Pietenpol, J. A., Kinzler, K. W., and Vogelstein, B., Definition of a consensus binding site for p53.Nature Genet., 1, 45–49 (1992).
Henson, J. W., Regulation of the glial-specific JC virus early promoter by the transcription factor Sp1.J. Biol. Chem., 269, 1046–1050 (1994).
Henson, J.W., Saffer, J., and Furneaux, The transcription factor Sp1 binds to the JC virus promoter and is selectively expressed in glial cells in human brain.Ann. Neurol., 32, 72–77 (1992).
Henson, J. W., Schnitker, B. L., Lee, T. S., and McAllister, J., Cell-specific activation of the glial-specific JC virus early promoter by large T antigen.J. Biol. Chem., 270, 13240–13245 (1995).
Jiang, D., Shrinivasan, A., Lozano, G., and Robbins, P.D., SV40 T antigen abrogates p53-mediated transcriptional activity.Oncogene, 8, 2805–2812 (1993).
Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B., and Craig, R. W., Participation of p53 protein in the cellular response to DNA damage.Cancer Res., 51, 6304–6311 (1991).
Kenny, S., Natarajan, V., Strike, D., Jhoury, G., and Salzman, N. P. JC virus enhancer-promoter active in human brain cells.Science, 226, 1337–1339 (1984).
Kim, H. S., Goncalves, N. M., and Henson, J. W., Glial cell-specific regulation of the JC virus early promoter by large T antigen.J. Virol., 74, 755–763 (2000).
Kim, H. S., Yang, C., and Kim, K. S., The cell-specific silencer region of the human dopamine beta-hydroxylase gene contains several negative regulatory elements.J. Neurochem., 71, 41–50 (1998).
Levine A. J., The p53 protein and its interactions with the oncogene products of the small DNA tumor viruses.Virology, 177 (2), 419–426 (1990).
Luckow, B. and Schutz, G., CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements.Nucleic Acids Res., 15, 5490 (1987).
Mack, D. H., Vartikar, J., Pipas, J. M., and Laimins, L. A. Specific repression of TATA-mediated but not initiator-mediated transcription by wild type p53.Nature, 363, 281–283 (1993).
Major, E. O., Amemiya, K., Tomatore, C. S., Houff, S. A., and Berger, J.R., Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelination disease of the human brain.Clin. Microbiol. Rev., 5, 49–73 (1992).
Rencic, A., Gordon, J., Otte, J., Curtis, M., Kovatich, A., Zoltick, P., Khalili, K., and Andrew, D., Detection of JC virus DNA sequence and expression of the viral oncoprotein, tumor antigen, in brain of immunocompetent patient with oligoastro-cytoma.,Proc. Natl. Acad. Sci. USA, 93, 7352–7357 (1996).
Staib, C., Pesch, J., Gerwig, R., Gerber, J. -K., Brehn, U., Stangl, A., and Grummt, F., p53 inhibits JC virus DNA replication in vivo and interacts with JC virus large T-antigen.Virology, 219, 237–246 (1996).
Weber, T and Major E.O., Progressive multifocal leukoence-phalopathy: molecular biology, pathogenesis and clinical impact.Intervirol., 40, 98–111 (1997).
Werness, B. A., Levine, A. J., and Howley, P. M., Association of human papillomavirus types 16 and 18 E6 proteins with p53.Science, 248(4951), 76–79 (1990).
Zu Rhein, G. M. and Chou, S.-M., Particles resembling papova viruses in human cerebral demyelinating disease.Science, 148, 1477–1479 (1965).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kim, HS., Woo, MS. Transcriptional regulation of the glial cell-specific JC virus by p53. Arch Pharm Res 25, 208–213 (2002). https://doi.org/10.1007/BF02976565
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF02976565