RAP46 Is a Negative Regulator of Glucocorticoid Receptor Action and Hormone-induced Apoptosis*
- Michael Kullmann‡§,
- Jean Schneikert‡§,
- Jürgen Moll‡,
- Stefanie Heck‡,
- Matthias Zeiner¶,
- Ulrich Gehring¶ and
- Andrew C. B. Cato‡‖
- From the ‡Forschungszentrum Karlsruhe, Institut für Genetik, Postfach 3640, D-76021 Karlsruhe and the¶Institut für Biologische Chemie, Universität Heidelberg, Im Neuenheimer Feld 501, D-69120 Heidelberg, Federal Republic of Germany
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.
Footnotes
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↵* The work was supported in part by a Boehringer Ingelheim studentship (to S. H.) and by Grant ERBFMBTCT961456 (to J. S.) from the TMR Program of the European Community.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ These two authors contributed equally to this work.
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↵‖ To whom correspondence should be addressed. Tel.: 49-7247-822146; Fax: 49-7247-823354; E-mail:andrew.cato{at}igen.fzk.de.
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↵1 The abbreviations used are: GR, glucocorticoid receptor; DBD, DNA-binding domain; GST, glutathioneS-transferase; NFI, nuclear factor I; CTF1, CCAAT-binding transcription factor; EMSA, electrophoretic mobility shift assay; RT-PCR, reverse transcription-polymerase chain reaction; MMTV, mouse mammary tumor virus; AR, androgen receptor.
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- Received October 28, 1997.
- Revision received March 10, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
