Subcellular Trafficking Signals of Constitutive Androstane Receptor: Evidence for a Nuclear Export Signal in the DNA-Binding Domain

Xia, Jun; Kemper, Byron

doi:10.1124/dmd.107.016493

Cited by 6 publications

(4 citation statements)

References 20 publications

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“…Serial-deletion and site-directed mutagenesis of CAR led to the identification of a leucine-rich motif (LXXLXXL) close to the C-terminal region, namely the xenobiotic response sequence (XRS), as the potential functional unit which dictates the nuclear translocation of CAR in response to various phenobarbital-type inducers (Zelko et al, 2001; Xia and Kemper, 2007). Nevertheless, these residues were not direct targets of either PP2A or PKA.…”

Section: Activation Of Carmentioning

confidence: 99%

Signaling control of the constitutive androstane receptor (CAR)

Yang

Wang

2014

Protein Cell

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The constitutive androstane receptor (CAR, NR1I3) plays a crucial role in the regulation of drug metabolism, energy homeostasis, and cancer development through modulating the transcription of its numerous target genes. Different from prototypical nuclear receptors, CAR can be activated by either direct ligand binding or ligand-independent (indirect) mechanisms both initiated with nuclear translocation of CAR from the cytoplasm. In comparison to the well-defined ligand-based activation, indirect activation of CAR appears to be exclusively involved in the nuclear translocation through mechanisms yet to be fully understood. Accumulating evidence reveals that without activation, CAR forms a protein complex in the cytoplasm where it can be functionally affected by multiple signaling pathways. In this review, we discuss recent progresses in our understanding of the signaling regulation of CAR nuclear accumulation and activation. We expect that this review will also provide greater insight into the similarity and difference between the mechanisms of direct vs. indirect human CAR activation.

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Section: Activation Of Carmentioning

confidence: 99%

Signaling control of the constitutive androstane receptor (CAR)

Yang

Wang

2014

Protein Cell

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“…The mPXR L385X mutant eliminated 46 amino acids from the C-terminus of mPXR, encompassing the XRS and the AF2 domain, while the 7 amino acid truncation (mPXR L425X ) was designed to disrupt AF2 function. The amino acid 61-62 phenylalanine to alanine mutations (i.e., mPXR F61/62A ) within the DNA binding domain of mPXR were derived by sequence homology to the glucocorticoid receptor [ Black et al, 2001 ] and the constitutive androstane receptor [ Xia and Kemper, 2007 ], where they have been identified as being critical for nuclear export to the cytoplasm.…”

Section: Resultsmentioning

confidence: 99%

A novel approach to investigate the subcellular distribution of nuclear receptors in vivo

et al. 2009

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Subcellular compartmentalisation and the intracellular movement of nuclear receptors are major regulatory steps in executing their transcriptional function.Though significant progress has been made in understanding these regulatory processes in cultured mammalian cells, such results have rarely been confirmed within cells of a living mammal. This article describes a simple, time-efficient approach to study the nuclear versus cytoplasmic accumulation of nuclear receptors and the regions of nuclear receptor proteins that govern subcellular trafficking within hepatocytes of live mice. Pregnane X receptor, a xenobiotic-activated member of the nuclear receptor family, was used to exemplify the approach. Using dual-labeled wild-type and mutant PXR expression constructs, we outline their in vivo delivery, simultaneous cellular expression, visualization and categorical classification within hepatocytes of live mice. Using this approach, we identified three mutants that had an altered subcellular distribution in the presence and absence of a PXR ligand. This novel in vivo method complements the current cell culture-based experimental systems in protein subcellular localisation studies.

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“…At the C-terminus, there is an activation function 2 (AF2) domain that is critical to transcription activation. Each DNA binding domain contains two zinc fingers that are conserved across species and between PXR and CAR (Xia and Kemper, 2007;Lichti-Kaiser et al, 2009). Upon ligand binding, both PXR and CAR form a complex with retinoid X receptor at the ligand binding domain as a heterotetramer with PXR or as a heterodimer with CAR.…”

Section: Introductionmentioning

confidence: 99%

Creation and Preliminary Characterization of Pregnane X Receptor and Constitutive Androstane Receptor Knockout Rats

et al. 2017

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The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of phase I (cytochrome P450s) and phase II metabolizing enzymes and transporter genes in response to stimulation from xenobiotics, including prescription drugs. PXR and CAR knockout and humanized mouse models have proven useful. However, the rat being bigger in size is a preferred model system for studying drug metabolism and pharmacokinetics. Here, we report the creation and preliminary characterization of PXR and CAR knockout rats and PXR/CAR double knockout rats. Whereas the expression of phase I and II enzymes and transporter genes were not upregulated by nuclear receptor-specific agonists pregnenlone-16-carbonitrile and 1,4-bis-[2-(3,5-dichloropyridyloxy)] benzene in the knockout rats, confirming the disruption of respective nuclear receptor(s), our data demonstrate that PXR appears to suppress the basal expression levels of Cyp2b2, Cyp3a23/3a1, Cyp3a2, Cyp3a18, and Ugt2b1 genes, while CAR maintains Cyp2b2 and Ugt2b1 and suppresses Cyp3a9 basal expression levels. In wild-type rats, agonist binding of the nuclear receptors relieves the suppression, and target genes are expressed at levels comparable to knockout rats, with or without drug treatment. Overall, our findings are in good agreement with data obtained from human primary hepatocytes, nuclear receptor knockout cell lines, and mouse knockout models. We believe these models are a useful complement to their mouse counterparts for drug development and as importantly, for functional studies on metabolic pathways involving nuclear receptors.

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Subcellular Trafficking Signals of Constitutive Androstane Receptor: Evidence for a Nuclear Export Signal in the DNA-Binding Domain

Cited by 6 publications

References 20 publications

Signaling control of the constitutive androstane receptor (CAR)

Signaling control of the constitutive androstane receptor (CAR)

A novel approach to investigate the subcellular distribution of nuclear receptors in vivo

Creation and Preliminary Characterization of Pregnane X Receptor and Constitutive Androstane Receptor Knockout Rats

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