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

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.

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Figure 1: CAR-β activity is inhibited by androstane derivatives.
Figure 2: Inhibition by androstanol is mediated by the LBD of CAR-β.
Figure 3: Androstanol interacts specifically with CAR-β to promote release of an SRC-1 fragment.

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Acknowledgements

We thank D. Russell and M. Mahendroo for discussions during this work; R.Miesfeld for an expression vector for the human androgen receptor; and S. Kliewer and I. Schulman for SRC-1 plasmids. This work was supported by the Howard Hughes Medical Institute (R.M.E.), March of Dimes (R.M.E.), CapCURE (R.M.E.), Tobacco-Related Disease Research Program (B.M.F.), The City of Hope National Medical Center/Beckman Research Institute (B.M.F.), and National Institutes of Health (D.D.M.). R.M.E. is an Investigator of the Howard Hughes Medical Institute at the Salk Institute for Biological Studies.

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Correspondence to Barry M. Forman.

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Forman, B., Tzameli, I., Choi, HS. et al. Androstane metabolites bind to and deactivate the nuclear receptor CAR-β. Nature 395, 612–615 (1998). https://doi.org/10.1038/26996

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