EXPRESSION OF THE NERVE GROWTH-FACTOR GENE IS CONTROLLED BY THE MICROTUBULE NETWORK

Colchicine, nocodazol, and vinblastine, three microtubule-disrupting d rugs, were shown to increase the levels of both nerve growth factor (N GF) mRNA and cell-secreted NGF protein in L929 cells, with levels of g lyceraldehyde-3-phosphate dehydrogenase (GAPDH) or amyloid precursor p rotein (APP) mRNAs remaining unaffected, Northern blot analysis demons trated that colchicine also increased NGF mRNA levels in rat primary a strocytes and mouse skin fibroblasts. The specificity of the effects o bserved was assessed by the fact that the microtubule-stabilizing agen t Taxotere(R), a semisynthetic compound structurally related to taxol, suppressed the effects of colchicine, whereas lumicolchicine, a colch icine derivative that has no action on the microtubule network, had no influence on NGF expression, Likewise, the disruption of the microfil ament network by cytochalasin B did not increase NGF mRNA levels in L9 29 cells, Furthermore, the increase in NGF gene expression observed fo llowing microtubule disruption depended on a cascade of events involvi ng at least one protein kinase, which is not down-regulated by phorbol ester, and on a pertussis toxin sensitive step, These results support the concept that tubulin and/or the microtubule cytoskeleton play an active role in the regulation of the NGF gene. (C) 1995 Wiley-Liss, In c.