We have reported that proteasomal inhibition of cultured rat cortical neurons leads to accumulation of detergent-insoluble polyubiquitinated species, formation of cytoplasmic inclusions and apoptotic death (SFN 2001:195.17). Here we examine the involvement of the tumor suppressor p53 in this model. p53 is known to play a role in some, but not all, models of proteasomal inhibition-induced death in cell lines. Whether it is regulated by the proteasome in neurons, and whether it is involved in proteasome inhibition-induced neuronal death or inclusion formation is unknown. 4-8 hrs after application of the specific proteasomal inhibitor lactacystin to E18 cortical neurons, total p53 protein levels increase, and p53 immunoreactivity accumulates in the nucleus. 24-36 hrs after lactacystin application, p53 is found within cytoplasmic inclusions. To test the requirement of p53 in these processes, we derived neurons from p53 +/+, +/-, and -/- mice. We found that lactacystin-induced death was dose-dependently attenua...