Human Leukemic Cell Line CEM C-7 Receptor and Inhibits Glucocorticoid-induced Apoptosis in the Modulator Inhibits Nuclear Translocation of the Glucocorticoid

Modulator is an endogenous low-molecular-weight regulator of both glucocorticoid and mineralocorticoid receptors as well as protein kinase C. Structural analysis of modulator purified to apparent homogeneity suggests that it is a novel ether aminophosphoglyceride. In this report, we show that modulator inhibits cytosolic human glucocorticoid receptor (GR) complex activation as measured by DNA-cellulose binding. In addi tion, modulator blocks glucocorticoid-induced nuclear translocation of the GR in intact human leukemic (CEM C-7) cells, as illustrated by ¡iiiiiiunocytochemical localization. Furthermore, we demonstrate that modula tor, by blocking the activation and subsequent translocation of GR, in hibits glucocorticoid-mediated apoptosis, characterized by chromatin condensation, internucleosomal DNA fragmentation, and cell death in glucocorticoid-sensitive CEM C-7 cells. Modulator inhibits glucocorti coid-induced C-/HVCgene repression and glucocorticoid receptor gene up-regulation. These data suggest that modulator functions to regulate the GR in intact cells as well as in cytosolic preparations. In addition, the inhibition of glucocorticoid-induced programmed cell death by modulator sheds light on the cellular function of modulator as well as on the mechanism by which apoptosis occurs in CEM C-7 cells.