SURVIVAL-PROMOTING ACTIVITY OF INHIBITORS OF CYCLIN-DEPENDENT KINASESON PRIMARY NEURONS CORRELATES WITH INHIBITION OF C-JUN KINASE-1

Cyclin-dependent kinases and mitogen-activated protein kinases have be en implicated in the regulation of cellular survival and apoptosis. We tested the effect of two mitogen-activated/cyclin-dependent kinase in hibitors, olomoucine and butyrolactone I, on the in vitro survival of chick embryonic neurons. Sensory, sympathetic, and ciliary neurons, wh en prepared at their respective time point of programmed cell death, c ould be rescued from apoptosis by both inhibitors in a dose-dependent fashion. In contrast, dividing sympathetic precursors underwent apopto sis when treated with olomoucine, but not butyrolactone I, at the same range of concentration. With similar potency, olomoucine and butyrola ctone I inhibited immunocomplex c-Jun kinase activity. Both substances inhibited neurite outgrowth in a dose-dependent manner; developmental ly younger neurons were more sensitive to this effect than older ones. These results suggest that certain mitogen-activated/cyclin-dependent kinases associated with cell division in neuronal precursors (i) may become essential components of the apoptotic machinery by the time neu rons reach their phase of naturally occurring cell death and (ii) may be necessary for neurite outgrowth during development. (C) 1997 Academ ic Press.