CYCLIN D1 IS AN ESSENTIAL MEDIATOR OF APOPTOTIC NEURONAL CELL-DEATH

Many neurons in the developing nervous system undergo programmed cell death, or apoptosis, However, the molecular mechanism underlying this phenomenon is largely unknown, In the present report, we present evide nce that the cell cycle regulator cyclin D1 is involved in the regulat ion of neuronal cell death, During neuronal apoptosis, cyclin D1-depen dent kinase activity is stimulated, due to an increase in cyclin D1 le vels, Moreover, artificial elevation of cyclin D1 levels is sufficient to induce apoptosis, even in non-neural cell types, Cyclin D1-induced apoptosis, like neuronal apoptosis, can be inhibited by 21 kDa E1B, B cl2 and pRb, but not by 55 kDa E1B, Most importantly, however, overexp ression of the cyclin D-dependent kinase inhibitor p16(INK4) protects neurons from apoptotic cell death, demonstrating that activation of en dogenous cyclin D1-dependent kinases is essential during neuronal apop tosis, These data support a model in which neuronal apoptosis results from an aborted attempt to activate the cell cycle in terminally diffe rentiated neurons.