P53 PLAYS A REGULATORY ROLE IN DIFFERENTIATION AND APOPTOSIS OF CENTRAL NERVOUS SYSTEM-ASSOCIATED CELLS

This study demonstrated the involvement of the tumor suppressor protei n p53 in differentiation and programmed cell death of neurons and olig odendrocytes, two cell types that leave the mitotic cycle early in dev elopment and undergo massive-scale cell death as the nervous system ma tures. We found that primary cultures of rat oligodendrocytes and neur ons, as well as of the neuronal PC12 pheochromocytoma cell line, const itutively express the p53 protein. At critical points in the maturatio n of these cells in vitro, the subcellular localization of p53 changes : during differentiation it appears mainly in the nucleus, whereas in mature differentiated cells it is present mainly in the cytoplasm. The se subcellular changes were correlated with changes in levels of immun oprecipitated p53. Infection of cells with a recombinant retrovirus en coding a C-terminal p53 miniprotein (p53 DD), previously shown to act as a dominant negative inhibitor of endogenous wild-type p53 activity, inhibited the differentiation of oligodendrocytes and of PC12 cells a nd protected neurons from spontaneous apoptotic death. These findings suggest that p53, upon receiving appropriate signals, is recruited int o the nucleus, where it plays a regulatory role in directing primary n eurons, oligodendrocytes, and PC12 cells toward either differentiation or apoptosis in vitro.