Identification, tissue expression, and glucocorticoid responsiveness of alternative first exons of the human glucocorticoid receptor.

Transcripts for the human glucocorticoid receptor (NR3C1) are known to contain alternative first exons 1A1, 1A2, and 1A3 from the distal promoter or 1D, 1E, 1B, 1F, 1C, or 1H from the proximal promoter. Here, we report two additional alternative first exons identified by Rapid amplification of cDNA ends (RACE)-PCR. The first, exon 1I, starts approximately 700 bp downstream of the splice donor site of the longest form of exon 1A, 1A3, considerably extending the known distal promoter region with a region containing conserved transcription factor-binding sites as well as a potential glucocorticoid response element (GRE) that differs from the consensus GRE in only two positions.

Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemia.

The ability of glucocorticoids (GCs) to kill lymphoid cells led to their inclusion in essentially all chemotherapy protocols for lymphoid malignancies, particularly childhood acute lymphoblastic leukemia (ALL). GCs mediate apoptosis via their cognate receptor and subsequent alterations in gene expression. Previous investigations, including expression profiling studies with subgenome microarrays in model systems, have led to a number of attractive, but conflicting, hypotheses that have never been tested in a clinical setting.

Glucocorticoid-induced apoptosis and glucocorticoid resistance in acute lymphoblastic leukemia.

Glucocorticoids (GC) induce cell cycle arrest and apoptosis in lymphoid cells, and therefore constitute a central component in the treatment of lymphoid malignancies, particularly childhood acute lymphoblastic leukemia (ALL). In spite of its clinical significance and considerable efforts in many laboratories, however, the molecular basis of GC-induced apoptosis and the clinically important resistance phenomenon remains poorly defined. The anti-leukemic GC effects are critically dependent upon sufficient expression of the GC receptor (GR) throughout the response.