2 WAVES OF CYCLIN-B AND PROLIFERATING CELL NUCLEAR ANTIGEN EXPRESSIONDURING DOPAMINE-TRIGGERED NEURONAL APOPTOSIS

The neurotransmitter dopamine is capable of inducing apoptosis in post mitotic sympathetic neurons via its oxidative metabolites. To detect g enes whose expression is transcriptionally regulated during the early stages of dopamine-triggered apoptosis, we applied the differential di splay method to cultured sympathetic neurons, One of the up-regulated genes was identified as cyclin B2, which exhibited two waves of induct ion and destruction, both at the mRNA and protein levels, resembling t he sequential oscillations typical of two successive mitotic events in proliferating cells. The time window between the two waves was charac terized by a change in expression of other cell-cycle stage-specific g enes, and oscillations in proliferating cell nuclear antigen and alter ations in cyclin A were observed. Cyclin D1 and cyclin-dependent kinas es were undetected and no sign of active DNA synthesis could be observ ed, indicating that activation of cell-cycle components is incomplete In comparison with a normal cell cycle, temporal expression profile of these mediators was unsynchronized. Whereas the first wave of cell-cy cle changes occurred prior to the commitment of the cells to the death process and could be tolerated by the cells, the second wave of chang es coincided with the death commitment point. Our findings indicate th at inappropriate and incomplete activation of some cell cycle-related genes in postmitotic neurons occurs during dopamine-triggered neuronal apoptosis.