In the current work, we studied how variations in extracellular zinc concentrations modulate different steps involved in nuclear factor B (NF-B) activation in human neuroblastoma IMR-32 cells. Cells were incubated in media containing varying concentrations of zinc (1.5, 5, 15, and 50 M). Within 3 h, the intracellular zinc content was lower in cells exposed to 1.5 and 5 M, compared with the other groups. Low intracellular zinc concentrations were associated with the activation of NF-B, based on high levels of IB⣠phosphorylation, low IB⣠concentrations, and high NF-B binding activity in total cell fractions. However, the active dimer accumulated in the cytosol, as shown by a low ratio of nuclear/cytosolic NF-B binding activity. This altered nuclear translocation was accompanied by a decreased transactivation of an endogenous NF-B-driven gene (ikba) and of a reporter gene (pNF-B-luc). In cells with low intracellular zinc concentrations, a low rate of in vitro tubulin polymerization was measured compared with the other groups. We conclude that low intracellular zinc concentrations induce tubulin depolymerization, which may be one signal for NF-B activation. However, NF-B nuclear translocation is impaired, which inhibits the transactivation of NF-B-driven genes. This could affect cell survival, and be an important factor in certain zinc deficiency-associated pathologies.