Bag-1M is a component of the in vivo DNA-glucocorticoid receptor complex at hormone-regulated promoter

Abstract

Molecular chaperones and cochaperones are known to participate in nuclear receptor-mediated gene expression in addition to providing the appropriate conformation for hormone binding. It has been reported that Bag-1M (Bcl-2 associated athanogene 1M) downregulates the transactivation function of the glucocorticoid receptor (GR). Here, we demonstrate that Bag-1M downregulates the glucocorticoid function via binding to distinct amino acid sequences in the hinge region of the GR. In cells expressing the human metallothionein IIa gene, overexpression of Bag-1M resulted in an in vivo dissociation of the DNA-receptor complex and a decrease in glucocorticoid-mediated transcription, indicating that this cochaperone acts as a negative regulator of GR action. In Bag-1M-expressing cells, this cochaperone is recruited with the GR to genomic hormone response element following glucocorticoid treatment. In line with this, small interfering RNA knockdown of the cellular level of Bag-1M enhanced DNA binding by the GR, resulting in a robust increase in transcriptional activity. These findings identify a regulatory mechanism, downstream of hormone binding, used by Bag-1M for attenuating GR action in response to its changing cellular levels.