Involvement of nuclear factor kappa B in c-myc induction by tubulin polymerization inhibitors

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