INTERACTION OF BAG-1 WITH RETINOIC ACID RECEPTOR AND ITS INHIBITION OF RETINOIC ACID-INDUCED APOPTOSIS IN CANCER-CELLS

BAG-1 (also known as RAP46) is an anti-apoptotic protein, which has be en shown previously to interact with a number of nuclear hormone recep tors, including receptors for glucocorticoid, estrogen, and thyroid ho rmone. We show here that BAG-I also interacts with retinoic acid recep tor (RAR). Gel retardation assays demonstrated that in vitro translate d BAG-1 protein could effectively inhibit the binding of RAR but not r etinoid X receptor (RXR) to a number of retinoic acid (RA) response el ements (RAREs), A glutathione S-transferase-BAG-1 fusion protein also specifically bound RAR but not RXR. Interaction of BAG-I and RAR could also be demonstrated by yeast two-hybrid assays. In transient transfe ction assays, co-transfection of BAG-1 expression plasmid inhibited th e transactivation activity of RAR/RXR heterodimers but not RXR/RXR hom odimers. When stably expressed in breast cancer cell lines, BAG-1 inhi bited binding of RAR/RXR heterodimer to a number of RAREs and suppress ed RA-induced growth inhibition and apoptosis. In addition, RA-induced suppression of Bcl-2 expression was abrogated by overexpression of BA G-1. These results demonstrate that BAG-1 can regulate retinoid activi ties through its interaction with RAR and suggest that elevated levels of BAG-I protein could potentially contribute to retinoid resistance in cancer cells.