GLUCOCORTICOID-INDUCED APOPTOSIS OF HUMAN LEUKEMIC-CELLS IS CAUSED BYTHE REPRESSIVE FUNCTION OF THE GLUCOCORTICOID RECEPTOR

Induction of apoptosis in lymphocytes, which may account for the thera peutic effects of glucocorticoids in various diseases including leukem ia, depends on the glucocorticoid receptor. However, the events leadin g from the activated receptor to cell lysis are not understood. A prev ailing hypothesis postulates induction of so-called 'lysis genes' by t he activated receptor. In this study, we show that an activation-defic ient glucocorticoid receptor mutant is as effective as the wildtype re ceptor in repression of AP-1 activity, inhibition of interleukin-2 pro duction, inhibition of c-myc expression and induction of apoptosis. Fu rthermore, we show that retinoic acid can also induce apoptosis in the se cells through the retinoic acid receptor, whose repressive function s but not target site specificity, are similar to those of the glucoco rticoid receptor. Therefore, the primary effect of the receptor in glu cocorticoid-mediated apoptosis correlates with transcriptional repress ion rather than activation and could be mediated by interference with other transcription factors required for cell survival.