The p53 tumor suppressor protein plays a key role in regulating cell cycle progression and apoptosis. Neuronal apoptosis resulting from DNA damage, hypoxia, and oxidative injury is mediated by p53. Using mixed cerebrocortical cultures from wild type (p53+/+) and p53 null (p53-/-) mice, we have now shown that neuronal apoptosis induced by the HIV coat protein gp120 also requires p53 (see Guo et al., 2003 SFN abstract). In contrast to p53+/+ cultures, HIV/gp120 does not induces caspase-3 enzymatic activity in p53-/- cultures, as measured by a fluorogenic substrate cleavage assay. Furthermore, caspase-3 cleavage products visualized by immunoreactivity for caspase-3-cleaved amyloid precursor protein, did not accumulate in neurons from p53-/- mice. Despite these findings, neurons and microglia from both genotypes develop increased immunoreactivity for activated caspase-3 after gp120 exposure. These findings suggest that in this system, p53 propagates its apoptotic action downstream of caspase-3 activation, perh...