Many activities of neuronal cells, such as synaptic transmission, inflammation, neuroprotection, and neurotoxicity, are regulated by the activity of the transcription factor nuclear factor-kappaB (NF-kappaB). In resting cells, NF-kappaB activity is present both in the cytoplasm, as an inducible-inactive complex, and in the nucleus as a constitutive form. The activation of its inducible form is related to processing of IkappaB(s), which occurs through the proteasome. To understand whether NF-kappaB is involved in the survival of cerebellar granule cells (CGCs) maintained under conditions of mild depolarization (25 mM KCl), these cells were treated with different proteasome inhibitors. The results presented show that these pharmacological tools reduce CGC survival with changes in nuclear morphology and induction of apoptosis. Furthermore, we demonstrate that PSI-induced apoptosis is reverted by inhibitors of transcription and translation, as well as by specific caspase inhibitors. These issues are also associated with a redistribution of NF-kappaB, in that a reduced amount of nuclear NF-kappaB and an increased p65 cytoplasmic level have been observed. Finally, we propose that, at least in part, p65 metabolism could also be regulated by the ubiquitin-proteasome complex. Altogether, the results presented define an important role for NF-kappaB in maintainig CGC survival.