BAG-1 family of cochaperones in the modulation of nuclear receptor action.

BAG-1 is a family of cochaperones consisting of at least four polypeptides BAG-1L, BAG-1M/RAP46, BAG-1 and p29. These proteins are translated from the same mRNA at alternative translation initiation sites. They possess conserved carboxy-terminal sequences which enable them to bind and inhibit the action of the molecular chaperone Hsp70/Hsc70. BAG-1 was the first member in the family of the BAG-1 proteins to be isolated. It was identified as an anti-apoptotic protein because of its ability to bind and augment the activity of the anti-death protein, Bcl-2. Since then other BAG-1 proteins have been identified and shown to interact with several cellular factors including nuclear receptors. Recent findings show that the effect of the BAG-1 proteins on nuclear receptors ranges from inhibition to enhancement of the transactivation functions of the receptors. Available data on the negative regulation of glucocorticoid receptor (GR) action by the BAG-1 proteins identify two modes of action: inhibition of the hormone binding activity of the GR and a more direct nuclear action at the level of regulation of the transactivation function of the receptor. In the latter case, the BAG-1 proteins repress DNA binding by the GR in a process that requires prior binding of Hsp70/Hsc70 to the receptor. Positive regulatory action of the BAG-1 proteins on nuclear receptors has also been reported which may involve yet other mechanisms. This review puts together recent findings on the action the BAG-1 proteins and presents them as a novel group of regulators of action of nuclear receptor.