p53 Regulation of Neural Precursor Cell Death

Regulation of neural precursor cell (NPC) death is important for both normal nervous system development and brain tumor formation. Previously by using primary NPC culture, we showed that genotoxin‐induced NPC death required p53‐dependent gene transcription, while staurosporine, a broad spectrum protein kinase inhibitor, induced NPC death in a p53 transcription‐independent manner. Here we used C17.2 cells, a mouse cerebellar NPC line, with high endogenous p53 expression, to further characterize p53 function in NPC death. The genotoxin‐induced caspase‐3 activation in C17.2 was inhibited by cycloheximide (CHX), a protein synthesis inhibitor. In contrast, CHX did not inhibit staurosporine‐induced caspase‐3 activation. Genotoxic agents increased nuclear p53 immunoreactivity, while staurosporine induced cytoplasmic p53 accumulation. The increase of cytoplasmic p53 after exposure to staurosporine was not inhibited by leptomycin B, an inhibitor of CRM1 dependent nuclear export. Phosphorylation of p53 on ser 15 was highly increased after genotoxic injury, but not staurosporine treatment. Deficiency of ataxia‐telangiectaisa mutated (ATM), which phosphorylates p53 on ser 15 after DNA damage, decreased bleomycin induced NPC death, but did not prevent staurosporine‐induced NPC death. These results suggest that genotoxins induce p53 transcription‐dependent NPC death, while staurosporine induces p53 transcription‐independent NPC death. Whether differential posttranslational modification of p53 leads to its different subcellular localization after genotoxin or staurosporine exposure requires further investigation. Supported by NS 41962