RAP46 is a negative regulator of glucocorticoid receptor action and hormone-induced apoptosis.
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.
Kullmann
M
M
Forschungszentrum Karlsruhe, Institut für Genetik, Postfach 3640, D-76021 Karlsruhe, Federal Republic of Germany.
Schneikert
J
J
Moll
J
J
Heck
S
S
Zeiner
M
M
Gehring
U
U
Cato
A C
AC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics*; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D051379:Mice; D011090:Polyenes / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D020123:Sirolimus; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D011090:Polyenes; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D003907:Dexamethasone; D020123:Sirolimus