Bag‐1M inhibits the transactivation of the glucocorticoid receptor via recruitment of corepressors

Abstract

a b s t r a c tThe Bcl-2 associated athanogene 1M (Bag-1M) is known to repress the transactivation of the glucocorticoid receptor (GR). We report here that Bag-1M inhibits the action of GR via recruitment of corepressors, including nuclear receptor corepressor (NcoR) and silencing mediator for retinoic acid and thyroid hormone receptor (SMRT), and histone deacetylase (HDAC)3 to the genomic response element of a glucocorticoid-regulated human metallothionein IIa (hMTIIa) gene. A mutant GR lacking the interaction with BAG-1M fails to recruit the corepressors NcoR and SMRT. RNAi-mediated knock down of corepressors and the use of HDAC inhibitor relieved Bag-1M-induced repression on the transactivation of the GR. In addition, Bag-1M is not involved in the degradation of the receptor. These findings indicate a novel mechanism by which Bag-1M acts as a corepressor and downregulates the activity of the GR. Structured summary:

Glucocorticoid receptor mediated suppression of natural killer cell activity: Identification of associated deacetylase and corepressor molecules

“…While such associations have been documented, we believe this work to be the first to demonstrate interactions among all three proteins, GR, SMRT, and HDAC1, and also the first to demonstrate such in natural killer cells. Others have shown that GR interacts with HDAC2 [36] and HDAC3 [37], as well as NCoR [37]. Contrary to those studies, these data demonstrate that GR does not appear to interact with NCoR, HDACs 2 or 3 in YT-Indy cells during Dex treatment.…”

“…As GR has been shown to interact with both NCoR and SMRT [37], the preference for one corepressor over the other may be due to differences in the subcellular environment among different cell types. Interaction between hormone nuclear receptors like GR and corepressors depend on a number of factors, including the direct binding between GR and the corepressor’s interacting domains, as well as the composition of the corepressor complex.…”

“…The initial increase coincided with the increase in HDAC1. HDACs 1 and 2 are known to associate with each other [37] in multiple protein complexes; thus, the initial retention of HDAC1 may also result in the initial increase in HDAC2 in the nucleus. Then, as increasing levels of ligand bound GR enter the nucleus (peaking at 4 hours of treatment), GR recruitment of HDAC1 may cause HDAC1 to dissociate from HDAC2.…”

BAG-1 suppresses expression of the key regulatory cytokine transforming growth factor β (TGF-β1) in colorectal tumour cells

“…This is the first evidence that BAG-1 occupies the gene promoter of a key growth regulatory cytokine, although it is likely that the regulation of TGFB1 gene expression involves BAG-1 as part of a multi-protein complex. For example, recent data identified BAG-1 as part of a trimeric complex [44], where glucocorticoid-mediated transcription was regulated by BAG-1 mediated recruitment of co-repressors [45]. Interestingly, a previous study has shown TGFB1 expression to be modulated by the p65 subunit of NF-κB [46] and BAG-1 has recently been identified as a regulator of NF-κB signalling [12,22].…”

Chaperones for proper androgen action – a plethora of assistance to androgen receptor function

“…BAG-1 proteins are co-chaperones that are involved in the regulation of SHRs. Different BAG-1 proteins exert varying effects on SHRs, ranging from inhibition, as shown for GR, to enhancement of the transactivation function [50] . In PCa, BAG-1 is often overexpressed and enhances AR activity [39] .…”