Abstract
IN T cells, cyclosporin A (CsA) exerts its immunosuppressive effect by preventing transcriptional induction of the expression of interleukin(IL)-2. This is achieved by a mechanism that involves binding of a CsA–cyclophilin complex to calcineurin, which in turn inhibits the phosphatase-controlled translocation of transcription factor NFAT to the nucleus1–8. We have previously identified IL-3 as an autocrine oncogenic regulator in tumour cell lines generated by introducing the v-H-ras oncogene into IL-3-dependent mast cells9–12. Here we report that CsA specifically blocks autocrine tumour cell growth. The mechanism involves down-regulation of IL-3 expression by destabilization of the messenger RNA and requires ongoing transcription. Transcripts from exogenous IL-3 genes lacking the (A + U)-rich element (ARE) in the 3' untranslated terminal repeat could not be destabilized, suggesting that at least part of this sequence, which is known to mediate decay of short-lived mRNA13, participates in a CsA-sensitive regulatory mechanism.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Krönke, M. et al. Proc. natn. Acad. Sci. U.S.A. 81, 5214–5218 (1984).
Flanagan, W. M., Corthésy, B., Bram, R. J. & Crabtree, G. R. Nature 352, 803–807 (1991).
Sigal, N. H. & Dumont, F. J. A. Rev. Immun. 10, 519–537 (1992).
O'Keefe, S. J., Tamura, J., Kincaid, R. L., Tocci, M. J. & O'Neill, E. A. Nature 357, 692–694 (1992).
Clipstone, N. A. & Crabtree, G. R. Nature 357, 695–697 (1992).
Schreiber, S. L. & Crabtree, G. R. Immun. Today 13, 136–142 (1992).
McCaffrey, P. G., Perrino, B. A., Soderling, T. R. & Rao, A. J. biol. Chem. 268, 3747–3752 (1993).
Liu, J. Immun. Today 14, 290–295 (1993).
Nair, A. P. K. et al. Molec. cell. Biol. 9, 1183–1190 (1989).
Diamantis, I. D., Nair, A. P. K., Hirsch, H. H. & Moroni, C. Proc. natn. Acad. Sci. U.S.A. 86, 9299–9302 (1989).
Nair, A. P. K., Hirsch, H. H. & Moroni, C. Oncogene 7, 1963–1972 (1992).
Hirsch, H. H., Nair, A. P. K. & Moroni, C. J. exp. Med. 178, 403–411 (1993).
Shaw, G. & Kamen, R. Cell 46, 659–667 (1986).
Erb, P., Grogg, D., Troxler, M., Kennedy, M. & Fluri, M. J. Immun. 144, 790–795 (1990).
Wodnar-Filipowicz, A. & Moroni, C. Proc. natn. Acad. Sci. U.S.A. 87, 777–781 (1990).
Campbell, H. D., Ymer, S., Fung, M. & Young, I. G. Eur. J. Biochem. 150, 297–304 (1985).
Cockerill, P. N., Shannon, M. F., Bert, A. G., Ryan, G. R. & Vadas, M. A. Proc. natn. Acad. Sci. U.S.A. 90, 2466–2470 (1993).
Wodnar-Filipowicz, A., Heusser, C. & Moroni, C. Nature 339, 150–152 (1989).
Abrams, J. S. & Pearce, M. K. J. Immun. 140, 131–137 (1988).
Ball, P. E., Conroy, M. C., Heusser, C., Davis, J. M. & Conscience, J. F. Differentiation 24, 74–78 (1983).
Karasuyama, H. & Melchers, F. Eur. J. Immun. 18, 97–104 (1988).
Gough, N. M. et al. Nature 309, 763–767 (1984).
Kelso, A. & Gough, N. M. Growth Factors 1, 165–177 (1989).
Noma, Y. et al. Nature 319, 640–646 (1986).
Van Snick, J. et al. Eur. J. Immun. 18, 193–197 (1988).
Yokota, T. et al. Proc. natn. Acad. Sci. U.S.A. 82, 68–72 (1985).
Andrejauskas, E. & Moroni, C. EMBO J. 8, 2575–2581 (1989).
Blochlinger, K. & Diggelmann, H. Molec. cell. Biol. 4, 2929–2931 (1984).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nair, A., Hahn, S., Banholzer, R. et al. Cyclosporin A inhibits growth of autocrine tumour cell lines by destabilizing interleukin-3 mRNA. Nature 369, 239–242 (1994). https://doi.org/10.1038/369239a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/369239a0
This article is cited by
-
p53 downregulates Down syndrome‐associated DYRK1A through miR‐1246
EMBO reports (2011)
-
The ARE-dependent mRNA-destabilizing activity of BRF1 is regulated by protein kinase B
The EMBO Journal (2004)
-
A novel mechanism of tumor suppression by destabilizing AU-rich growth factor mRNA
Oncogene (2003)
-
Search for oncogenic regulators in an autocrine tumor model using differential display PCR: Identification of novel candidate genes including the calcium channel mtrp6
Oncogene (1999)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.