PROTEASOMES PLAY AN ESSENTIAL ROLE IN THYMOCYTE APOPTOSIS

Cell death in many different organisms requires the activation of prot eolytic cascades involving cytosolic proteases. Here we describe a nov el requirement in thymocyte cell death for the 20S proteasome, a highl y conserved multicatalytic protease found in all eukaryotes. Specific inhibitors of proteasome function blocked cell death induced by ionizi ng radiation, glucocorticoids or phorbol ester. In addition to inhibit ing apoptosis, these signals prevented the cleavage of poly(ADP-ribose ) polymerase that accompanies many cell deaths. Since overall rates of protein degradation were not altered significantly during cell death in thymocytes, these results suggest that the proteasome may either de grade regulatory protein(s) that normally inhibit the apoptotic pathwa y or may proteolytically activate protein(s) that promote cell death.