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Vol. 59, Issue 5, 1165-1170, May 2001

Involvement of Nuclear Factor kappa B in c-Myc Induction by Tubulin Polymerization Inhibitors

V. Bourgarel-Rey, S. Vallee, O. Rimet, S. Champion, D. Braguer, A. Desobry, C. Briand, and Y. Barra

Unité Mixte de Recherche Centre National de la Recherche Scientifique 6032, Faculté de Pharmacie, Marseille, France

We showed previously that microtubule disassembly by vinblastine induces the proto-oncogene c-myc in epithelial mammary HBL100 cells (Bourgarel-Rey et al., 2000). In this study, we demonstrate that vinblastine treatment in these cells, in contrast to what was observed with the colon adenocarcinoma cell line HT29-D4, activated the transcription factor NFkappa B, which has been involved in c-myc regulation. The microtubule disassembly also induced Ikappa B degradation. Using transient transfection analysis, we show that the trans-activation of c-myc by vinblastine was decreased when NFkappa B binding sites on c-myc promoter were mutated. Additionally, we demonstrate that microtubule dissolution trans-activated a thymidine kinase-CAT construct containing an NFkappa B binding site at -1180 to -1080 bp relative to the P1 promoter. Thus, vinblastine up-regulates the enhancer activity of the NFkappa B binding site. These results suggest that microtubule disassembly induced by vinblastine can trans-activate the c-myc oncogene through NFkappa B. Taking into consideration the paradoxical roles of both c-myc and NFkappa B in proliferation or apoptosis, this data reveals the complex action mechanism of this microtubule interfering agent.


Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics



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