JUN AND JNK KINASE ARE ACTIVATED IN THYMOCYTES IN RESPONSE TO VM26 AND RADIATION BUT NOT GLUCOCORTICOIDS

In order to establish what role members of the activating protein-1 (A P-1) gene families, i.e., c-fos, c-jun, junB, and junD, play in thymic apoptosis, we have analyzed changes in their expression in response t o three different agents: a glucocorticoid analog dexamethasone, an in hibitor of topoisomerase II teniposide VM26, and gamma radiation. All three agents induced thymic death at a similar rate and with the same morphological and biochemical features. There was a rapid and transien t increase in the steady-state mRNA level of junB and c-fos genes in a ll treatments, including control cultures, reminiscent rather of cellu lar stress response to the environmental changes than to the apoptotic stimuli. On the other hand, treatments with the DNA-damaging agents, VM26 and gamma radiation, resulted in superinduction of the c-jun mRNA and in the activation of the stress response signaling pathway of c-J un N-terminal kinase. Gene transcription ceased completely in cells wi th fragmented DNA and the down-regulation of genes such as junD and tu bulin was reflective of the thymocytes' commitment to apoptosis. The D NA-binding activities of the serum response factors, cyclic AMP respon se element binding proteins, and AP-1 factors, indicative of their tra nscriptional competence, were compromised shortly after induction of a poptosis regardless of the agent employed, consistent with previously reported enhancement in cellular proteolysis which is an essential com ponent of the apoptotic cell death. (C) 1997 Academic Press.