E4BP4 facilitates glucocorticoid-evoked apoptosis of human leukemic CEM cells via upregulation of Bim

Mouse E4BP4 was ectopically expressed in CEM-C1-15 cells, resulting in sensitization to GC-evoked apoptosis in correlation with restoration of E4BP4 and Bim upregulation. shRNA mediated modest knockdown of E4BP4 in CEM-C7-14 cells resulted in concomitant reduction in Bim expression, although GC-evoked fold-induction and sensitivity to apoptosis was similar to parental cells.Data presented here suggest that GC-mediated upregulation of E4BP4 facilitates Bim upregulation and apoptosis of CEM cells. Since the Bim promoter does not contain any consensus GRE or EBPRE sequences, induction of Bim may be a secondary response.Glucocorticoids (GCs) are known to evoke human lymphoid cell apoptosis [1-3] primarily by binding to and modulating the transcriptional activity of the GC receptor (GR) [4]. GCs possess immunosuppressive and anti-inflammatory properties and serve as effective therapeutic agents for different forms of leukemia [5], asthma, rheumatoid arthritis, and irritable bowel syndrome [6]. In order to exploit the full therapeutic potential of GCs, GC/GR-mediated gene regulation and its impact on various cellular processes needs to be better understood. To this end, we and others have studied GR-dependent gene regulation by microarray-based transcriptional profiling [7-9]. A subset of genes were identified as those being upregulated selectively in human leukemic CEM cells susceptible to, but not in cells refractory to, GC-evoked apoptosis [7]. In this report, one of those genes, E4BP4, was evaluated for its role GC-evoked apoptosis.E4BP4 (adenovirus E4 binding protein 4), also called NFIL3 (nuclear factor, interleukin 3 regulated) is classified as a mammalian basic leucine zipper (bZIP) transcription factor and is closely related to the PAR (proline and acid rich) sub-family of bZIP transcription factors, although it lacks a PAR domain [10]. Vertebrate PAR family transcription factors include hepatic leukemia factor (HLF), D-box binding protein (DBP), and thyrotroph e