DIRECT INVOLVEMENT OF P53 IN PROGRAMMED CELL-DEATH OF OLIGODENDROCYTES

A covalent dimer of interleukin (IL)-2, produced in vitro by the actio n of a nerve-derived transglutaminase, has been shown previously to be cytotoxic to mature rat brain oligodendrocytes. Here we report that t his cytotoxic effect operates via programmed cell death (apoptosis) an d that the p53 tumor suppressor gene is involved directly in the proce ss. The apoptotic death of mature rat brain oligodendrocytes in cultur e following treatment with dimeric IL-2 was demonstrated by chromatin condensation and internucleosomal DNA fragmentation. The peak of apopt osis was observed 16-24 h after treatment, while the commitment to dea th was already observed after 3-4 h. An involvement of p53 in this pro cess was indicated by the shift in location of constitutively expresse d endogenous p53 from the cytoplasm to the nucleus, as early as 15 min after exposure to dimeric IL-2. Moreover, infection with a recombinan t retrovirus encoding a C-terminal p53 minoprotein, shown previously t o act as a dominant negative inhibitor of endogenous wild-type p53 act ivity, protected these cells from apoptosis.