Two waves of cyclin B and proliferating cell nuclear antigen expression during dopamine-triggered neuronal apoptosis

The neurotransmitter dopamine is capable of inducing apoptosis in postmitotic sympathetic neurons via its oxidative metabolites. To detect genes whose expression is transcriptionally regulated during the early stages of dopamine-triggered apoptosis, we applied the differential display method to cultured sympathetic neurons. One of the up-regulated genes was identified as cyclin B2, which exhibited two waves of induction and destruction, both at the mRNA and protein levels, resembling the sequential oscillations typical of two successive mitotic events in proliferating cells. The time window between the two waves was characterized by a change in expression of other cell-cycle stage-specific genes, and oscillations in proliferating cell nuclear antigen and alterations in cyclin A were observed. Cyclin D1 and cyclin-dependent kinases were undetected and no sign of active DNA synthesis could be observed, 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-cycle changes occurred prior to the commitment of the cells to the death process and could be tolerated by the cells, the second wave of changes coincided with the death commitment point. Our findings indicate that inappropriate and incomplete activation of some cell cycle-related genes in postmitotic neurons occurs during dopamine-triggered neuronal apoptosis.