ROLE OF C-JUN INDUCTION IN THE GLUCOCORTICOID-EVOKED APOPTOTIC PATHWAY IN HUMAN LEUKEMIC LYMPHOBLASTS

Accumulated evidence suggests that the transcription factor AP-1 (Jun/ Fos) is involved in apoptotic cell death. The expression of members of the AP-1 family in CEM cell clones exposed to the glucocorticoid dexa methasone (Dex) has been investigated, Dex is known to cause apoptosis of lymphoid cells in general and of sensitive human lymphoid CEM cell clones in particular. This study finds that Dex induces c-jun mRNA an d cJun protein in cells of the sensitive clone CEM-C7 and of the lysis -sensitive CEM hybrid clone H10. CEM-C7 cells were screened for severa l other Jun/Fos family proteins. Both cFos and JunD were expressed but were unaffected by the steroid, and JunB was not detected. In the con tinual presence of Dex the induction of cJun began about 6 h after add ition of Dex, reached a maximum by 24 h, and plateaued for 72 h, while cell death did not begin until 24-48 h. In clone CEM-C1 cells, which contain glucocorticoid receptor (GR) but are resistant to lysis by Dex , the basal, and even the fully induced, cJun levels are below the bas al levels in CEM-C7 and H10 cells. To test the hypothesis that cJun pl ays an important role in steroid-evoked apoptosis, stable transfectant s expressing Dex-regulable antisense c-jun RNA were established. Mass cultures of these cells showed reduced sensitivity to Dex, and in thre e of three clones tested, complete resistance to Dex was obtained. Thi s occurred even though endogenous genes (GR, c-jun) normally responsiv e to Dex were still inducible, indicating that the GR and basic glucoc orticoid response apparatus were intact. It is concluded that Dex indu ces cJun levels in sensitive CEM cells before cell death and that this induction plays a role in the apoptotic process.