Analysis of Glucocorticoid Target Genes

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To determine the genes responsible for mediating the effects of glucocorticoids (GCs) on leukemic cells, the transcriptional changes in GC-sensitive human pre-B leukemia 697 cells during GC-induced apoptosis were monitored using oligonucleotide microarrays. Of 12,000 genes examined for their response to GC, 93 genes were induced and 28 genes were repressed, many of which are known to be implicated in signal transduction, growth arrest and transcription. These included the signal transduction-related genes encoding SOCS1, SOCS2, FKBP5, DSCR1, p561ck and four protein kinase phosphatases. Growth arrest-related genes encoding p19^<INK4d> and several Myc inhibitors were induced in response to the GC treatment. Anti-proliferative- or apoptosis-related genes encoding BTG1, BTG2 and granzyme A (GZMA) were also found to be transcriptionally up-regulated by GC. In addition, the regulation of genes encoding the glucocorticoid receptor (GR) and steroid receptor coactivator-1 suggested autoregulation of a GC-mediated signaling pathway. These genes were upregulated by GC even in the presence of an inhibitor of protein synthesis, cycloheximide, indicating that they are direct target genes of GR. DSCR1 is reported to have four isoforms, each of which has a distinct first exon, E1 to E4. Among these isoforms, the one with E1 was selectively upregulated by GC. GZMA and FKBP5 have a cluster of putative glucocorticoid response elements (GREs) in intron 1 and intron 2, respectively, that was identified to be responsible for the response to GC. They were composed of one complete (A/T)G(A/T)(A/T)C(A/T) sequence surrounded by two incomplete (A/T)G(A/T)(A/T)C(A/T) sequence separated by one to four nucleotides. DSCR1, however, did not have a functional GRE upstream or downstream of exon 1. These studies may lead to improved therapeutic uses of GCs in leukemia and lymphoma based upon the expression of these GC target genes.