Differential glucocorticoid receptor-mediated transcription mechanisms.
Nuclear receptors such as the glucocorticoid receptor (GR) are ligand-dependent transcription factors that mediate transcription of target genes by recruiting factors that modulate chromatin structure. In this study, curcumin, a compound known to inhibit GR-mediated transcription, was used to examine the different mechanisms by which GR regulates transcription. The mechanisms of transcription regulation of metallothioneine-2A (MT2A) and solute carrier family 19 member 2 (SLC19A2), two GR target genes where the hormone-dependent gene activation is inhibited or unaffected by curcumin treatment, respectively, were analyzed by chromatin immunoprecipitation and RT-PCR experiments. The data suggest that the loss of hormone-dependent MT2A gene expression is due to the inhibition of continued transcription activity after initial assembly of the transcription machinery. In contrast, the hormone-dependent SLC19A2 gene expression is maintained because the continued transcription output after assembly of transcription machinery is unaffected by curcumin. These results suggest that the two GR target genes use alternate mechanisms to regulate expression levels at the level of continued transcription output after transcription machinery assembly.
Chromatin and Gene Expression Section, Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Sayura
S
Aoyagi
Trevor K
TK
Archer
D003474:Curcumin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D026901:Membrane Transport Proteins / Q000096:biosynthesis*; D008668:Metallothionein / Q000096:biosynthesis*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; C491053:MT2A protein, human; D026901:Membrane Transport Proteins; D011965:Receptors, Glucocorticoid; C120043:SLC19A2 protein, human; D008668:Metallothionein; D003474:Curcumin