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-I (AP-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 to three different agents: a glucocorticoid analog dexamethasone, an inhibitor 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 transient increase in the steady-state mRNA level of junB and c-fos genes in all treatments, including control cultures, reminiscent rather of cellular 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-Jun N-terminal kinase. Gene transcription ceased completely in cells with fragmented DNA and the down-regulation of genes such as junD and tubulin was reflective of the thymocytes' commitment to apoptosis. The DNA-binding activities of the serum response factors, cyclic AMP response element binding proteins, and AP-1 factors, indicative of their transcriptional competence, were compromised shortly after induction of apoptosis regardless of the agent employed, consistent with previously reported enhancement in cellular proteolysis which is an essential component of the apoptotic cell death.