Identification of novel direct transcriptional targets of glucocorticoid receptor.
Transcription of the genes Granzyme A (GZMA), FK506 binding protein 51 (FKBP5), and Down syndrome critical region gene 1 (DSCR1) is upregulated in leukemic cells upon treatment with glucocorticoids (GCs). Several lines of evidence suggest that these genes are implicated in GC-induced apoptosis upstream of the Bcl-2 family of proteins. 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 glucocorticoid receptors. DSCR1 is reported to have four isoforms, each of which has a distinct first exon, E1-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 introns 1 and 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) sequences 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.
U
M
M
Department of Genetics, National Research Institute for Child Health and Development, Tokyo, Japan.
Shen
L
L
Oshida
T
T
Miyauchi
J
J
Yamada
M
M
Miyashita
T
T
D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004314:Down Syndrome; D024202:Electrophoretic Mobility Shift Assay; D005091:Exons / Q000235:genetics; D005938:Glucocorticoids; D053804:Granzymes; D018841:HSP90 Heat-Shock Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007438:Introns / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D020218:Response Elements; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation; D000099159:Tacrolimus Binding Protein 5
D003513:Cycloheximide; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D053804:Granzymes; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors; D011965:Receptors, Glucocorticoid; D012697:Serine Endopeptidases; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C108612:RCAN1 protein, human; C509212:GZMA protein, human