Skip to main content
Biochemical Journal logoLink to Biochemical Journal
. 1996 Sep 15;318(Pt 3):883–888. doi: 10.1042/bj3180883

Melanotransferrin gene expression in melanoma cells is correlated with high levels of Jun/Fos family transcripts and with the presence of a specific AP1-dependent ternary complex.

A Rozé-Heusse 1, M L Houbiguian 1, C Debacker 1, M M Zakin 1, N Duchange 1
PMCID: PMC1217700  PMID: 8836133

Abstract

The involvement of the transcription factor AP1 in the regulation of melanotransferrin (MTf) gene expression was investigated. MTf, also known as p97, is a tumour-associated antigen that is overproduced in most melanomas. Its gene expression is under the control of an enhancer element containing two AP1 binding sites. By Northern analysis, we demonstrate that MTf mRNA is detected at various levels in melanoma SK-MEL-28 cells and that its greatest expression coincides with the presence of large amounts of jun and fos transcripts. Gel retardation assays revealed that the induction of expression of these proto-oncogenes is correlated with increased AP1 binding activity and that a region of the MTf enhancer is involved in the formation of a ternary AP1-dependent complex, implicating a second nuclear factor whose binding characteristics are similar to those of nuclear factor of activated T cells (NF-AT). In transient expression experiments, the activity resulting from ternary complex formation was high and specific to melanoma cells. These data provide a possible explanation for the mechanisms of AP1 factor family involvement in MTf up-regulation in melanoma cells.

Full Text

The Full Text of this article is available as a PDF (380.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Angel P., Allegretto E. A., Okino S. T., Hattori K., Boyle W. J., Hunter T., Karin M. Oncogene jun encodes a sequence-specific trans-activator similar to AP-1. Nature. 1988 Mar 10;332(6160):166–171. doi: 10.1038/332166a0. [DOI] [PubMed] [Google Scholar]
  2. Angel P., Hattori K., Smeal T., Karin M. The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell. 1988 Dec 2;55(5):875–885. doi: 10.1016/0092-8674(88)90143-2. [DOI] [PubMed] [Google Scholar]
  3. Angel P., Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129–157. doi: 10.1016/0304-419x(91)90011-9. [DOI] [PubMed] [Google Scholar]
  4. Binétruy B., Smeal T., Karin M. Ha-Ras augments c-Jun activity and stimulates phosphorylation of its activation domain. Nature. 1991 May 9;351(6322):122–127. doi: 10.1038/351122a0. [DOI] [PubMed] [Google Scholar]
  5. Boshart M., Klüppel M., Schmidt A., Schütz G., Luckow B. Reporter constructs with low background activity utilizing the cat gene. Gene. 1992 Jan 2;110(1):129–130. doi: 10.1016/0378-1119(92)90456-y. [DOI] [PubMed] [Google Scholar]
  6. Boyle W. J., Smeal T., Defize L. H., Angel P., Woodgett J. R., Karin M., Hunter T. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell. 1991 Feb 8;64(3):573–584. doi: 10.1016/0092-8674(91)90241-p. [DOI] [PubMed] [Google Scholar]
  7. Brooks G., Goss M. W., East J. A., Hart I. R. Growth of melanocytic cells is associated with down-regulation of protein kinase C alpha, delta, and epsilon isoforms. Possible role of diacylglycerol. J Biol Chem. 1993 Nov 15;268(32):23868–23875. [PubMed] [Google Scholar]
  8. Brooks G., Wilson R. E., Dooley T. P., Goss M. W., Hart I. R. Protein kinase C down-regulation, and not transient activation, correlates with melanocyte growth. Cancer Res. 1991 Jun 15;51(12):3281–3288. [PubMed] [Google Scholar]
  9. Brown J. P., Woodbury R. G., Hart C. E., Hellström I., Hellström K. E. Quantitative analysis of melanoma-associated antigen p97 in normal and neoplastic tissues. Proc Natl Acad Sci U S A. 1981 Jan;78(1):539–543. doi: 10.1073/pnas.78.1.539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chiu R., Angel P., Karin M. Jun-B differs in its biological properties from, and is a negative regulator of, c-Jun. Cell. 1989 Dec 22;59(6):979–986. doi: 10.1016/0092-8674(89)90754-x. [DOI] [PubMed] [Google Scholar]
  11. Cockerill P. N., Bert A. G., Jenkins F., Ryan G. R., Shannon M. F., Vadas M. A. Human granulocyte-macrophage colony-stimulating factor enhancer function is associated with cooperative interactions between AP-1 and NFATp/c. Mol Cell Biol. 1995 Apr;15(4):2071–2079. doi: 10.1128/mcb.15.4.2071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Devary Y., Gottlieb R. A., Lau L. F., Karin M. Rapid and preferential activation of the c-jun gene during the mammalian UV response. Mol Cell Biol. 1991 May;11(5):2804–2811. doi: 10.1128/mcb.11.5.2804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Duchange N., Ochoa A., Plowman G. D., Rozé A., Amdjadi M., Zakin M. M. Identification of an enhancer involved in the melanoma-specific expression of the tumor antigen melanotransferrin gene. Nucleic Acids Res. 1992 Jun 11;20(11):2853–2859. doi: 10.1093/nar/20.11.2853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dérijard B., Hibi M., Wu I. H., Barrett T., Su B., Deng T., Karin M., Davis R. J. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994 Mar 25;76(6):1025–1037. doi: 10.1016/0092-8674(94)90380-8. [DOI] [PubMed] [Google Scholar]
  15. Fisher G. J., Datta S. C., Talwar H. S., Wang Z. Q., Varani J., Kang S., Voorhees J. J. Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature. 1996 Jan 25;379(6563):335–339. doi: 10.1038/379335a0. [DOI] [PubMed] [Google Scholar]
  16. Gutman A., Wasylyk B. The collagenase gene promoter contains a TPA and oncogene-responsive unit encompassing the PEA3 and AP-1 binding sites. EMBO J. 1990 Jul;9(7):2241–2246. doi: 10.1002/j.1460-2075.1990.tb07394.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hoey T., Sun Y. L., Williamson K., Xu X. Isolation of two new members of the NF-AT gene family and functional characterization of the NF-AT proteins. Immunity. 1995 May;2(5):461–472. doi: 10.1016/1074-7613(95)90027-6. [DOI] [PubMed] [Google Scholar]
  18. Jain J., McCaffrey P. G., Valge-Archer V. E., Rao A. Nuclear factor of activated T cells contains Fos and Jun. Nature. 1992 Apr 30;356(6372):801–804. doi: 10.1038/356801a0. [DOI] [PubMed] [Google Scholar]
  19. Kennard M. L., Richardson D. R., Gabathuler R., Ponka P., Jefferies W. A. A novel iron uptake mechanism mediated by GPI-anchored human p97. EMBO J. 1995 Sep 1;14(17):4178–4186. doi: 10.1002/j.1460-2075.1995.tb00091.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Larue L., Dougherty N., Mintz B. Genetic predisposition of transgenic mouse melanocytes to melanoma results in malignant melanoma after exposure to a low ultraviolet B intensity nontumorigenic for normal melanocytes. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9534–9538. doi: 10.1073/pnas.89.20.9534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. McCaffrey P. G., Luo C., Kerppola T. K., Jain J., Badalian T. M., Ho A. M., Burgeon E., Lane W. S., Lambert J. N., Curran T. Isolation of the cyclosporin-sensitive T cell transcription factor NFATp. Science. 1993 Oct 29;262(5134):750–754. doi: 10.1126/science.8235597. [DOI] [PubMed] [Google Scholar]
  22. Michel G., Kemeny L., Homey B., Ruzicka T. FK506 in the treatment of inflammatory skin disease: promises and perspectives. Immunol Today. 1996 Mar;17(3):106–108. doi: 10.1016/0167-5699(96)80599-8. [DOI] [PubMed] [Google Scholar]
  23. Nerlov C., Rørth P., Blasi F., Johnsen M. Essential AP-1 and PEA3 binding elements in the human urokinase enhancer display cell type-specific activity. Oncogene. 1991 Sep;6(9):1583–1592. [PubMed] [Google Scholar]
  24. Nolan G. P. NF-AT-AP-1 and Rel-bZIP: hybrid vigor and binding under the influence. Cell. 1994 Jun 17;77(6):795–798. doi: 10.1016/0092-8674(94)90126-0. [DOI] [PubMed] [Google Scholar]
  25. Northrop J. P., Ho S. N., Chen L., Thomas D. J., Timmerman L. A., Nolan G. P., Admon A., Crabtree G. R. NF-AT components define a family of transcription factors targeted in T-cell activation. Nature. 1994 Jun 9;369(6480):497–502. doi: 10.1038/369497a0. [DOI] [PubMed] [Google Scholar]
  26. Offringa R., Gebel S., van Dam H., Timmers M., Smits A., Zwart R., Stein B., Bos J. L., van der Eb A., Herrlich P. A novel function of the transforming domain of E1a: repression of AP-1 activity. Cell. 1990 Aug 10;62(3):527–538. doi: 10.1016/0092-8674(90)90017-9. [DOI] [PubMed] [Google Scholar]
  27. Pulverer B. J., Kyriakis J. M., Avruch J., Nikolakaki E., Woodgett J. R. Phosphorylation of c-jun mediated by MAP kinases. Nature. 1991 Oct 17;353(6345):670–674. doi: 10.1038/353670a0. [DOI] [PubMed] [Google Scholar]
  28. Rao A. NF-ATp: a transcription factor required for the co-ordinate induction of several cytokine genes. Immunol Today. 1994 Jun;15(6):274–281. doi: 10.1016/0167-5699(94)90007-8. [DOI] [PubMed] [Google Scholar]
  29. Rose T. M., Plowman G. D., Teplow D. B., Dreyer W. J., Hellström K. E., Brown J. P. Primary structure of the human melanoma-associated antigen p97 (melanotransferrin) deduced from the mRNA sequence. Proc Natl Acad Sci U S A. 1986 Mar;83(5):1261–1265. doi: 10.1073/pnas.83.5.1261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rozé A., Zakin M. M., Duchange N. Regulation of melanotransferrin gene in melanoma cells. Analysis of the enhancer region. Biochim Biophys Acta. 1995 Feb 21;1260(3):301–307. doi: 10.1016/0167-4781(94)00208-k. [DOI] [PubMed] [Google Scholar]
  31. Sassone-Corsi P. Goals for signal transduction pathways: linking up with transcriptional regulation. EMBO J. 1994 Oct 17;13(20):4717–4728. doi: 10.1002/j.1460-2075.1994.tb06797.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Schreiber E., Matthias P., Müller M. M., Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. doi: 10.1093/nar/17.15.6419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Schüle R., Evans R. M. Cross-coupling of signal transduction pathways: zinc finger meets leucine zipper. Trends Genet. 1991 Nov-Dec;7(11-12):377–381. doi: 10.1016/0168-9525(91)90259-s. [DOI] [PubMed] [Google Scholar]
  34. Testa U., Pelosi E., Peschle C. The transferrin receptor. Crit Rev Oncog. 1993;4(3):241–276. [PubMed] [Google Scholar]
  35. Yamanishi D. T., Graham M., Buckmeier J. A., Meyskens F. L., Jr The differential expression of protein kinase C genes in normal human neonatal melanocytes and metastatic melanomas. Carcinogenesis. 1991 Jan;12(1):105–109. doi: 10.1093/carcin/12.1.105. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES