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Modulator Inhibits Nuclear Translocation of the Glucocorticoid Receptor and Inhibits Glucocorticoid-induced Apoptosis in the Human Leukemic Cell Line CEM C-7¹

Department of Pharmacology and the Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

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 addition, modulator blocks glucocorticoid-induced nuclear translocation of the GR in intact human leukemic (CEM C-7) cells, as illustrated by immunocytochemical localization. Furthermore, we demonstrate that modulator, by blocking the activation and subsequent translocation of GR, inhibits glucocorticoid-mediated apoptosis, characterized by chromatin condensation, internucleosomal DNA fragmentation, and cell death in glucocorticoid-sensitive CEM C-7 cells. Modulator inhibits glucocorticoid-induced c-myc gene 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.

¹ Supported by Research Grants DK 42353 and DK 44441 from the NIH to G. L.

² Present address: Women's Health Research Institute, Wyeth-Ayerst Laboratories, Radnor, PA 19087.

³ To whom requests for reprints should be addressed, at Department of Pharmacology and the Jefferson Cancer Institute, Thomas Jefferson University, 10th and Locust Streets, Philadelphia, PA 19107.

Received 7/15/94. Accepted 11/21/94.