RAP46 Is a Negative Regulator of Glucocorticoid Receptor Action and Hormone-induced Apoptosis

Abstract

RAP46 was first identified by its ability to bind the glucocorticoid receptor. It has since been reported to bind several cellular proteins, including the anti-apoptotic protein Bcl-2, but the biological significance of these interactions is unknown. Here we show that RAP46 binds the hinge region of the glucocorticoid receptor and inhibits DNA binding and transactivation by the receptor. We further show that overexpression of RAP46 in mouse thymoma S49.1 cells inhibits glucocorticoid-induced apoptosis. Conversely, glucocorticoid-induced apoptosis and transactivation were enhanced after treating S49.1 cells with the immunosuppressant rapamycin, which down-regulates cellular levels of BAG-1, the mouse homolog of RAP46. The effect of rapamycin can, however, be overcome by overexpression of RAP46. These results together identify RAP46 as a protein that controls glucocorticoid-induced apoptosis through its negative regulatory action on the transactivation property of the glucocorticoid receptor.

AtBAG6, a novel calmodulin-binding protein, induces programmed cell death in yeast and plants

“…[60][61][62][63][64][65][66][67][68][69] The functional diversity of BAG domain proteins is paralleled by an abundance of genes of this family throughout evolution, with homologs identified in a variety of organisms, including yeast, worm, invertebrates, amphibians, mammals, and plants. 21,59,60,70 Database searches indicate the presence of eight genes that encode proteins with the BAG domain in Arabidopsis thaliana.…”

BAG-1 accelerates cell motility of human gastric cancer cells

“…BAG-1 can promote Ras-independent activation of Raf-1 kinase (Wang et al, 1996). Moreover, BAG-1 modulates the activities of the p53-inducible factor Siah-1 and some steroid hormone receptors (Matsuzawa et al, 1998), promoting cell growth and survival and conferring resistance to retinoids and antiandrogens (Liu et al, 1998;Kullmann et al, 1998). Thus, multiple functions have been attributed to BAG-1, and essentially all of these could contribute to malignant cell behaviors.…”

BAG‐1, An Anti‐Apoptotic Tumour Marker

“…RAP46 binds the hinge region of the glucocorticoid receptor, inhibits DNA binding and transactivation by the receptor, and suppresses glucocorticoid-induced apoptosis (10). BAG-1 also binds to androgen receptor and markedly increases its transcriptional activity (11).…”