scholarly journals The Orphan Nuclear Receptor DAX-1 Functions as a Potent Corepressor of the Constitutive Androstane Receptor (NR1I3)

2012 ◽  
Vol 82 (5) ◽  
pp. 918-928 ◽  
Author(s):  
Elizabeth M. Laurenzana ◽  
Tao Chen ◽  
Malavika Kannuswamy ◽  
Brian E. Sell ◽  
Stephen C. Strom ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Constitutive Androstane Receptor ◽  
Orphan Nuclear Receptor

scholarly journals Deletion of Nuclear Receptor Constitutive Androstane Receptor CAR Increases Anxiety and Lowers Androgen Levels

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A807-A807
Author(s):  
Juan P Hernandez ◽  
Anjana Asokakumar ◽  
Rui Xiao ◽  
David D Moore ◽  
Sayeepriyadarshini Anakk
Keyword(s):  
Nuclear Receptor ◽  
Leydig Cells ◽  
Constitutive Androstane Receptor ◽  
Serum Testosterone ◽  
Transcriptional Networks ◽  
Testis Weight ◽  
Orphan Nuclear Receptor ◽  
Plus Maze ◽  
Marble Burying ◽  
Androgen Levels

Abstract The orphan nuclear receptor, Constitutive Androstane Receptor (CAR, NR1I3) is primarily known to regulate the transcriptional networks involved in detoxification. We have identified a novel extra-hepatic role of CAR in regulating androgen levels and modulating testis function. Previous data has revealed that CAR activation by estradiol and inactivation by androstanol suggests an intricate link between sex hormones and CAR. We investigated control wild type and CARKO mice and found that the serum testosterone and androstenedione levels were lower in the absence of CAR. As expected, we did not find any induction of the genes in the detoxification machinery including, Cyp3a, Cyp2b, Cyp2c family, Sult2a1 and Mrp. The decrease in the androgen levels in the CARKO mice is consistent with decrease in the anogenital distance, increased anxiety as measured by marble burying and elevated plus maze but no change in testis weight. H&E staining of CARKO mice shows accumulation of fat in the Leydig cells and lower numbers of Leydig cells which are in accordance with the loss of androgen levels. In addition, we will examine the consequence of reduced androgen and the hypothalamus-pituitary-gonadal axis in the CARKO mice.

Xenobiotic induction of cytochrome P450 2B1 (CYP2B1) is mediated by the orphan nuclear receptor constitutive androstane receptor (CAR) and requires steroid co-activator 1 (SRC-1) and the transcription factor Sp1

2001 ◽  
Vol 355 (1) ◽  
pp. 71-78 ◽  
Author(s):  
Roongsiri MUANGMOONCHAI ◽  
Despina SMIRLIS ◽  
Siew-Cheng WONG ◽  
Mina EDWARDS ◽  
Ian R. PHILLIPS ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cytochrome P450 ◽  
Nuclear Receptor ◽  
Constitutive Androstane Receptor ◽  
Proximal Promoter ◽  
Orphan Nuclear Receptor ◽  
Primary Hepatocytes ◽  
Transcription Factor Sp1 ◽  
Transformed Cell Lines ◽  
Xenobiotic Induction

The constitutive androstane receptor (CAR) activates the expression of a reporter gene attached to the phenobarbital-response element (PBRE) of the cytochrome P450 2B1 (CYP2B1) gene in response to the barbiturate phenobarbital and the plant product picrotoxin. The xenobiotic-mediated increase in transactivation occurs in transfected primary hepatocytes and in liver transfected by biolistic-particle-mediated DNA transfer, but not in the transformed cell lines HepG2, CV-1 and HeLa, which support only constitutive activation of gene expression by CAR. Steroid co-activator 1 (SRC-1) enhances both constitutive and xenobiotic-induced CAR-mediated transactivation via the CYP2B1 PBRE in transfected primary hepatocytes. The nuclear receptor 1 (NR1) site of the PBRE is sufficient for CAR-mediated transactivation, but additional sequences within the PBRE, and hence the proteins that bind to them, are required for the interaction of CAR with SRC-1. The NR2 site of the PBRE binds proteins other than CAR, including an unidentified nuclear receptor heterodimerized with retinoid X receptor α. By binding to the proximal promoter of CYP2B1, the transcription factor Sp1 increases both basal transcription and xenobiotic-induced expression via the PBRE. Thus induction of CYP2B1 expression by xenobiotics is mediated by the nuclear receptor CAR and, for optimal expression, requires SRC-1 and Sp1.

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