Microarray analysis uncovers the induction of the proapoptotic BH3-only protein Bim in multiple models of glucocorticoid-induced apoptosis

Abstract

Despite being one of the earliest recognized and most clinically relevant forms of apoptosis, little is known about the transcriptional events that mediate glucocorticoid-induced apoptosis. Therefore, we used oligonucleotide microarrays to identify the pattern of dexamethasone-induced changes in gene expression in two well characterized models of glucocorticoid-induced apoptosis, the murine lymphoma cell lines S49.A2 and WEH17.2. Dexamethasone treatment induced a diverse set of gene changes that evolved over a 24-h period preceding the onset of cell death. These include previously reported changes in the expression of genes regulating prosurvival signals mediated by c-Myc and NFκB. Unexpectedly, we discovered that glucocorticoid treatment increases expression of the gene encoding Bim, a BH3-only member of the Bcl-2 family that is capable of directly activating the apoptotic cascade. Induction of Bim was confirmed by immunoblotting not only in S49.A2 and WEH17.2 cells but also in the human leukemia cell line CEM-C7 and in primary murine thymocytes. All three prototypical isoforms of Bim (BimEL, BimL, and BimS) were induced by dexamethasone. Because elevated expression of Bim initiates the execution phase of cell death, this report that Bim is induced by dexamethasone provides novel insight into the mechanism through which glucocorticoid-mediated changes in gene expression induce apoptosis in lymphoid cells.