Androstane metabolites bind to and deactivate the nuclear receptor CAR-β

Barry M. Forman (), Iphigenia Tzameli, Hueng-Sik Choi, Jasmine Chen, Devendranath Simha, Wongi Seol, Ronald M. Evans and David D. Moore
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Barry M. Forman: The City of Hope National Medical Center
Iphigenia Tzameli: Baylor College of Medicine
Hueng-Sik Choi: Hormone Research Center, Chonnam National University
Jasmine Chen: The City of Hope National Medical Center
Devendranath Simha: Wellman 913, Massachusetts General Hospital
Wongi Seol: Dana-Farber Cancer Institute
Ronald M. Evans: The Howard Hughes Medical Institute, The Salk Institute for Biological Studies
David D. Moore: Baylor College of Medicine

Nature, 1998, vol. 395, issue 6702, 612-615

Abstract: Abstract The orphan receptor CAR-β (ref. 1) binds DNA as a heterodimer with the retinoid-X receptor and activates gene transcription in a constitutive manner. Here we show that, in contrast to the classical nuclear receptors, the constitutive activity of CAR-β results from a ligand-independent recruitment of transcriptional co-activators. While searching for potential ligands of CAR-β, we found that the steroids androstanol and androstenol inhibit the constitutive activity of CAR-β. This effect is stereospecific: only 3α-hydroxy, 5α-reduced androstanes are active. These androstanes do not interfere with heterodimerization or DNA binding of CAR-β; instead, they promote co-activator release from the ligand-binding domain. These androstane ligands are examples of naturally occurring inverse agonists2,3 that reverse transcriptional activation by nuclear receptors. CAR-β (constitutive androstane receptor-β), therefore, defines an unanticipated steroidal signalling pathway that functions in a manner opposite to that of the conventional nuclear receptor pathways.

Date: 1998
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DOI: 10.1038/26996

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