ACTIVATION OF JNK SAPK PATHWAY IS NOT DIRECTLY INHIBITORY FOR CELL-CYCLE PROGRESSION IN NIH3T3 CELLS/

In this study the induction of stress activated protein kinase (SAPK) activity by protein synthesis inhibitors was shown not to inhibit cell ular proliferation. Anisomycin induced strong SAPK activity at non-inh ibitory concentrations for either protein or DNA synthesis, while the other two inhibitors, emetine and cycloheximide, blocked cell cycle pr ogression without strong SAPK induction. With all three inhibitors, th e induction of SAPK activity was always accompanied by protein synthes is inhibition to some extent. Stimulation of mRNA expression of the ge nes c-jun, c-fos and c-myc correlated well with SAPK induction, but no t with cell cycle inhibition. With concentrations of each inhibitor ab le to block DNA synthesis, no induction of message for the cyclin depe ndent kinase inhibitor waf-1 was observed;,while induction of gadd45 m essage indicated that the cells might be responding to growth-arrest o r DNA damage. The inability of microinjected E2F/DP1 transcription fac tor proteins to overcome the inhibition of DNA synthesis induced by pr otein synthesis inhibitors indicate that blockage of an early event in cell cycle progression had occurred. These results indicate that the SAPK induction by protein synthesis inhibitors has no proliferative co nsequences.