Curcumin Derivatives Inhibit the Formation of Jun-Fos-DNA Complex Independently of their Conserved Cysteine Residues

  • Park, Chi-Hoon (Division of Chemistry and Molecular Engineering, Seoul National University) ;
  • Lee, Ju-Hyung (Division of Chemistry and Molecular Engineering, Seoul National University) ;
  • Yang, Chul-Hak (Division of Chemistry and Molecular Engineering, Seoul National University)
  • Published : 2005.07.31


Curcumin, a major active component of turmeric, has been identified as an inhibitor of the transcriptional activity of activator protein-1 (AP-1). Recently, it was also found that curcumin and synthetic curcumin derivatives can inhibit the binding of Jun-Fos, which are the members of the AP-1 family, to DNA. However, the mechanism of this inhibition by curcumin and its derivatives was not disclosed. Since the binding of Jun-Fos dimer to DNA can be modulated by redox control involving conserved cysteine residues, we studied whether curcumin and its derivatives inhibit Jun-Fos DNA binding activity via these residues. However, the inhibitory mechanism of curcumin and its derivatives, unlike that of other Jun-Fos inhibitors, was found to be independent of these conserved cysteine residues. In addition, we investigated whether curcumin derivatives can inhibit AP-1 transcriptional activity in vivo using a luciferase assay. We found that, among the curcumin derivatives examined, only inhibitors shown to inhibit the binding of Jun-Fos to DNA by Electrophoretic Mobility Shift Assay (EMSA) inhibited AP-1 transcriptional activity in vivo. Moreover, RT-PCR revealed that curcumin derivatives, like curcumin, downregulated c-jun mRNA in JB6 cells. These results suggest that the suppression of the formation of DNA-Jun-Fos complex is the main cause of reduced AP-1 transcriptional activity by curcuminoids, and that EMSA is a suitable tool for identifying inhibitors of transcriptional activation.


  1. Abate, C., Luk, D., Gentz, R., Rauscher, F. J. III. and Curran, T. (1990a) Expression and purification of the leucine zipper and DNA-binding domains of Fos and Jun: Both Fos and Jun contact DNA directly. Proc. Natl. Acad. Sci. USA 87, 1032-1036
  2. Abate, C., Patel, L., Rauscher, F. J. III. and Curran, T. (1990b) Redox regulation of fos and jun DNA-binding activity in vitro. Science 249, 1157-1161
  3. Ammon, H. P. and Wahl, M. A. (1991) Pharmacology of Curcuma longa. Plata. Med. 57, 1-7
  4. Angel, P., Hattori, K., Smeal, T. and Karin, M. (1988) The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell 55, 875-885
  5. Angel, P. and Karin, M. (1991) The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim. Biophys. Acta. 1072, 129-157
  6. Bhaumik, S., Anjum, R., Rangaraj, N., Pardhasaradhi, B. V. and Khar, A. (1999) Curcumin mediated apoptosis in AK-5 tumor cells involves the production of reactive oxygen intermediates. FEBS Lett. 456, 311-314
  7. Bohmann, D. and Tjian, R. (1989) Biochemical Analysis of Transcriptional Activation by Jun: differential activity of Cand v-Jun. Cell 59, 709-717
  8. Conney, A. H., Lysz, T., Ferraro, T., Abidi, T. F., Manchand, P. S., Laskin, J. D. and Huang, M. T. (1991) Inhibitory effect of curcumin and some related dietary components on tumor promotion and arachidonic acid metabolism in mouse skin. Adv. Enzyme Regul. 31, 385-396
  9. Devary, Y., Gottlieb, R. A., Lau, L. F. and Karin, M. (1991) Rapid and preferential activation of the c-jun gene during the mammalian UV response. Mol. Cell. Biol. 11, 2804-2811
  10. Devary, Y., Gottlieb, R. A., Smeal, T. and Karin, M. (1992) The Mammalian ultraviolet response is triggered by activation of src tyrosine kinases. Cell 71, 1081-1091
  11. Ding, M., Shi, X., Lu, Y., Huang, C., Leonard, S., Roberts, J., Antonini, J., Castranova, V. and Vallyathan, V. (2001) Induction of activator protein-1 through reactive oxygen species by crystalline silica in JB6 cells. J. Biol. Chem. 276, 9108-9114
  12. Distel, R. J., Ro, H. S., Rosen, B. S., Groves, D. L. and Spiegelman, B. M. (1987) Nucleoprotein complexes that regulate gene expression in adipocyte differentiation: direct participation of c-fos. Cell 49, 835-844
  13. Hahm, E. R., Cheon, G., Lee, J. H., Kim, B. J., Park, C. H. and Yang, C. H. (2002) New and known symmetrical curcumin derivatives inhibit the formation of Fos-Jun-DNA complex. Cancer Lett. 184, 89-96
  14. Han, S. S., Keum, Y. S., Soe, H. J. and Surh, Y. J. (2002) Curcumin suppresses activation of NF-$\kappa$B and AP-1 induced by phorbol ester in cultured human promyelocytic leukemia cells. J. Biochem. Mol. Biol. 35, 337-342
  15. Handel, M. L., Watts, C. K., DeFazio, A., Day, R. O. and Sutherland, R. L. (1995) Inhibition of AP-1 binding and transcription by gold and selenium involving conserved cysteine residues in Jun and Fos. Proc. Natl. Acad. Sci. USA 92, 4497-4501
  16. Huang, M. T., Deschner, E. E., Newmark, H. L., Wang, Z. Y., Ferraro, T. A. and Conney, A. H. (1992) Effect of dietary curcumin and ascorbyl palmitate on azoxymethanol-induced colonic epithelial cell proliferation and focal areas of dysplasia. Cancer Lett. 64, 117-121
  17. Huang, M. T., Lou, Y. R., Ma, W., Newmark, H. L., Reuhl, K. R. and Conney, A. R. (1994) Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice. Cancer Res. 54, 5841-5847
  18. Huang, T. S., Lee, S. C. and Lin, J. K. (1991) Suppression of cjun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells. Proc. Natl. Acad. Sci. USA 88, 5292-5296
  19. Kouzarides, T. and Ziff, E. (1988) The role of the leucine zipper in the fos-jun interaction. Nature 336, 646-651
  20. Lee, W., Mitchell, P. and Tjian, R. (1987) Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Cell 49, 741-752
  21. Mohan, R., Sivak, J., Ashton, P., Russo, L. A., Pham, B. Q., Kasahara, N., Raizman, M. B. and Fini, M. E. (2000) Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B. J. Biol. Chem. 275, 10405-10412
  22. Nikitovic, D., Holmgren, A. and Spyrou, G. (1998) Inhibition of AP-1 DNA binding by nitric oxide involving conserved cysteine residues in Jun and Fos. Biochem. Biophys. Res. Commun. 242, 109-112
  23. Ohtsu, H., Xiao, Z., Ishida, J., Nagai, M., Wang, H. K., Itokawa, H., Su, C. Y., Shih, C., Chiang, T., Chang, E., Lee, Y., Tsai, M. Y., Chang, C. and Lee, K. H. (2002) Antitumor Agents. 217. Curcumin analogues as novel androgen receptor antagonists with potential as anti-prostate cancer agents. J. Med. Chem. 45, 5037-5042
  24. Pabon, H. J. J. (1964) A synthesis of curcumin and related compounds. Rec. Trav. Chim. Pays. Bas. 83, 379-386
  25. Park, J. E., Lee, K. Y., Do, S. I. and Lee, S. S. (2002) Expression and characterization of B-1,4-galactosyltransferase from Neisseria meningitidis and Neisseria gonorrhoeae. J. Biochem. Mol. Biol. 35, 330-336
  26. Rahman, A., Shahabuddin, H. S. M., Parish, J. H. and Ainley, K. (1989) Strand scission in DNA induced by quercetin and Cu(II): role of Cu(I) and oxygen free radicals. Carcinogenesis 10, 1833-1839
  27. Rao, C. V., Rivenson, A., Simi, B. and Reddy, B. S. (1995) Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res. 55, 259-266
  28. Satoskar, R. R., Shah, S. J. and Shenoy, S. G. (1986) Evaluation of anti-inflammatory property of curcumin (dieferuloyl methane) in patients with postoperative inflammation. Int. J. Clin. Pharmacol. Ther. Toxicol. 24, 651-654
  29. Sharma, O. P. (1976) Antioxidant activity of curcumin and related compounds. Biochem. Pharmacol. 25, 1811-1812
  30. Shim, M. J., Kim, H. J., Yang S. J., Lee, I. S., Choi, H. I. and Kim, T. U. (2002) Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: possible involvement of p38 MAP kinase. J. Biochem. Mol. Biol. 35, 377-383
  31. Singh, A. K., Sidhu, G. S., Deepa, T. and Maheshwari, R. K. (1996) Curcumin inhibits the proliferation and cell cycle progression of human umbilical vein endothelial cell. Cancer Lett. 107, 109-115
  32. Srimal, R. C. and Dhawan, B. N. (1973) Pharmacology of diferuloyl methane (curcumin), a non-steroidal anti-inflammatory agent. J. Pharm. Pharmacol. 25, 447-452
  33. Sugiyama, Y., Kawakishi, S. and Osawa, T. (1996) Involvement of the beta-diketone moiety in the antioxidative mechanism of tetrahydrocurcumin. Biochem. Pharmacol. 52, 519-525
  34. Toda, S., Miyase, T., Arichi, H., Tanizawa, H. and Takiyano, Y. (1985) Natural antioxidants, III: antioxidative components isolated from rhizome of curcuma longa L. Chem. Pharm. Bull. 33, 1725-1728
  35. Zhang, F., Altorki, N. K., Mestre, J. R., Subbaramaiah, K. and Dannenberg, A. J. (1999) Curcumin inhibits cyclooxygenase-2 transcription in bile acid - and phorbol ester-treated human gastrointestinal epithelial cells. Carcinogenesis 20, 445-451

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