Abstract
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 NFκB, which has been involved in c-myc regulation. The microtubule disassembly also induced IκB degradation. Using transient transfection analysis, we show that thetrans-activation of c-myc by vinblastine was decreased when NFκB binding sites on c-myc promoter were mutated. Additionally, we demonstrate that microtubule dissolutiontrans-activated a thymidine kinase-CAT construct containing an NFκB binding site at −1180 to −1080 bp relative to the P1 promoter. Thus, vinblastine up-regulates the enhancer activity of the NFκB binding site. These results suggest that microtubule disassembly induced by vinblastine can trans-activate the c-myc oncogene through NFκB. Taking into consideration the paradoxical roles of both c-myc and NFκB in proliferation or apoptosis, this data reveals the complex action mechanism of this microtubule interfering agent.
Footnotes
- Received November 1, 2000.
- Accepted February 5, 2001.
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Send reprint requests to: Pr. Yves Barra, Faculté de Pharmacie, 27 Bd Jean Moulin, 13005 Marseille, France. E-mail:yves.barra{at}pharmacie.univ-mrs.fr
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V.B.-R. and S.B. contributed equally to this work
- The American Society for Pharmacology and Experimental Therapeutics
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