Neuronal apoptosis is involved in several pathological conditions of the brain. Using cDNA arrays, we observed upregulation of ubiquitin-binding protein p62 expression during serum withdrawal-induced apoptosis in Neuro-2a cells. We demonstrate here that the expression levels of p62 mRNA and protein were increased in Neuro-2a cells and cultured rat hippocampal neurons by different types of proapoptotic treatments, including serum deprivation, okadaic acid, etoposide, and trichostatin A. Ubiquitin-binding protein p62 is a widely expressed cytoplasmic protein of unclear function. The ability of p62 to bind noncovalently to ubiquitin and to several signalling proteins suggests that p62 may play a regulatory role connected to the ubiquitin system. Accordingly, we show that proteasomal inhibitors MG-132, lactacystin, and PSI caused a prominent upregulation of p62 mRNA and protein expression, with a concomitant increase in ubiquitinated proteins. To conclude, p62 upregulation appears to be a common event in neuronal apoptosis. Results also suggest that the induction of p62 expression by proteasomal inhibitors may be a response to elevated levels of ubiquitinated proteins, possibly constituting a protective mechanism.