Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta.
The orphan receptor CAR-beta 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-beta results from a ligand-independent recruitment of transcriptional co-activators. While searching for potential ligands of CAR-beta, we found that the steroids androstanol and androstenol inhibit the constitutive activity of CAR-beta. This effect is stereospecific: only 3alpha-hydroxy, 5alpha-reduced androstanes are active. These androstanes do not interfere with heterodimerization or DNA binding of CAR-beta; instead, they promote co-activator release from the ligand-binding domain. These androstane ligands are examples of naturally occurring inverse agonists that reverse transcriptional activation by nuclear receptors. CAR-beta (constitutive androstane receptor-beta), therefore, defines an unanticipated steroidal signalling pathway that functions in a manner opposite to that of the conventional nuclear receptor pathways.
The City of Hope National Medical Center, Duarte, California 91010, USA. bforman@gte.net
B M
BM
Forman
I
I
Tzameli
H S
HS
Choi
J
J
Chen
D
D
Simha
W
W
Seol
R M
RM
Evans
D D
DD
Moore
D000731:Androstanes / Q000378:metabolism*; D000732:Androstanols / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D000090702:Constitutive Androstane Receptor; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D013237:Stereoisomerism; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014162:Transfection
D000731:Androstanes; D000732:Androstanols; D000090702:Constitutive Androstane Receptor; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C000658:androstan-3-ol; C033936:androstane