Involvement of nuclear factor kappaB in c-Myc induction by tubulin polymerization inhibitors.
We showed previously that microtubule disassembly by vinblastine induces the proto-oncogene c-myc in epithelial mammary HBL100 cells. 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 NFkappaB, which has been involved in c-myc regulation. The microtubule disassembly also induced IkappaB degradation. Using transient transfection analysis, we show that the trans-activation of c-myc by vinblastine was decreased when NFkappaB binding sites on c-myc promoter were mutated. Additionally, we demonstrate that microtubule dissolution trans-activated a thymidine kinase-CAT construct containing an NFkappaB binding site at -1180 to -1080 bp relative to the P1 promoter. Thus, vinblastine up-regulates the enhancer activity of the NFkappaB binding site. These results suggest that microtubule disassembly induced by vinblastine can trans-activate the c-myc oncogene through NFkappaB. Taking into consideration the paradoxical roles of both c-myc and NFkappaB in proliferation or apoptosis, this data reveals the complex action mechanism of this microtubule interfering agent.
Bourgarel-Rey
V
V
Unité Mixte de Recherche Centre National de la Recherche Scientifique 6032, Faculté de Pharmacie, Marseille, France.
Vallee
S
S
Rimet
O
O
Champion
S
S
Braguer
D
D
Desobry
A
A
Briand
C
C
Barra
Y
Y
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001665:Binding Sites; D004742:Enhancer Elements, Genetic / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D019073:HT29 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D015739:Nocodazole / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D050257:Tubulin Modulators; D015854:Up-Regulation; D014747:Vinblastine / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D020672:I-kappa B Proteins; C000715470:MAS1 protein, human; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D050257:Tubulin Modulators; D014747:Vinblastine; D015739:Nocodazole