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Gene/Protein
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Target Concepts:
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Query: UMLS:C0406810 (
NAME
)
13,345
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
A wide range of xenobiotic compounds are metabolized by cytochrome P450 (CYP) enzymes, and the genes that encode these enzymes are often induced in the presence of such compounds. Here, we show that the nuclear receptor
CAR
can recognize response elements present in the promoters of xenobiotic-responsive CYP genes, as well as other novel sites.
CAR
has previously been shown to be an apparently constitutive
transactivator
, and this constitutive activity is inhibited by androstanes acting as inverse agonists. As expected, the ability of
CAR
to transactivate the CYP promoter elements is blocked by the inhibitory inverse agonists. However,
CAR
transactivation is increased in the presence of 1,4-bis[2-(3, 5-dichloropyridyloxy)]benzene (TCPOBOP), the most potent known member of the phenobarbital-like class of CYP-inducing agents. Three independent lines of evidence demonstrate that TCPOBOP is an agonist ligand for
CAR
. The first is that TCPOBOP acts in a dose-dependent manner as a direct agonist to compete with the inhibitory effect of the inverse agonists. The second is that TCPOBOP acts directly to stimulate coactivator interaction with the
CAR
ligand binding domain, both in vitro and in vivo. The third is that mutations designed to block ligand binding block not only the inhibitory effect of the androstanes but also the stimulatory effect of TCPOBOP. Importantly, these mutations do not block the apparently constitutive transactivation by
CAR
, suggesting that this activity is truly ligand independent. Both its ability to target CYP genes and its activation by TCPOBOP demonstrate that
CAR
is a novel xenobiotic receptor that may contribute to the metabolic response to such compounds.
...
PMID:The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR. 1075 80
Expression of cellular receptors determines viral tropism and limits gene delivery by viral vectors. Protein transduction domains (PTDs) have been shown to deliver proteins, antisense oligonucleotides, liposomes, or plasmid DNA into cells. In our study, we investigated the role of several PTD motifs in adenoviral infection. When physiologically expressed, a PTD from human immunodeficiency virus
transactivator
of transcription (Tat) did not improve adenoviral infection. We therefore fused PTDs to the ectodomain of the coxsackievirus-adenovirus receptor (
CAR
(ex)) to attach PTDs to adenoviral fiber knobs.
CAR
(ex)-Tat and
CAR
(ex)-VP22 allowed efficient adenoviral infection in nonpermissive cells and significantly improved viral uptake rates in permissive cells. Dose-dependent competition of
CAR
(ex)-PTD-mediated infection using
CAR
(ex) and inhibition experiments with heparin showed that binding of
CAR
(ex)-PTD to both adenoviral fiber and cellular glycosaminoglycans is essential for the improvement of infection.
CAR
(ex)-PTD-treated adenoviruses retained their properties after density gradient ultracentrifugation, indicating stable binding of
CAR
(ex)-PTD to adenoviral particles. Consequently, the mechanism of
CAR
(ex)-PTD-mediated infection involves coating of the viral fiber knobs by
CAR
(ex)-PTD, rather than placement of
CAR
(ex) domains on cell surfaces. Expression of
CAR
(ex)-PTDs led to enhanced lysis of permissive and nonpermissive tumor cells by replicating adenoviruses, indicating that
CAR
(ex)-PTDs are valuable tools to improve the efficacy of oncolytic therapy. Together, our study shows that
CAR
(ex)-PTDs facilitate gene transfer in nonpermissive cells and improve viral uptake at reduced titers and infection times. The data suggest that PTDs fused to virus binding receptors may be a valuable tool to overcome natural tropism of vectors and could be of great interest for gene therapeutic approaches.
...
PMID:Protein transduction domains fused to virus receptors improve cellular virus uptake and enhance oncolysis by tumor-specific replicating vectors. 1556 83
The detoxification and elimination of potentially toxic foreign and endogenous compounds depends on the concerted action of xenobiotic metabolizing enzymes. Nuclear hormone receptors (NHRs) have emerged as key regulators of the expression of these enzymes and his review focuses on the xenosenor
CAR
(Constitutive Androstane Receptor, NR1I3).
CAR
is highly expressed in the liver and the small intestine, two key tissues expressing xenobiotic metabolizing enzymes, and mediates the induction of their expression by the widely used antiepileptic drug, phenobarbital (PB) and the potent synthetic inducer 1, 4-bis-(2-(3, 5, -dichloropyridyloxy)) benzene (TCPOBOP). TCPOBOP is an agonist ligand for
CAR
. PB induces its nuclear translocation, which results in increased expression of
CAR
target genes since, unlike the classical, ligand-dependent nuclear receptors,
CAR
is an apparently constitutive
transactivator
. This constitutive activity is inhibited by the inverse agonist ligands androstanol and androstenol. The
CAR
mediated induction of the expression of xenobiotic metabolizing enzymes is generally protective, but can be deleterious if toxic metabolites are produced.
CAR
also has a protective role in the stress response elicited by hyperbilirubinemia, as well as lithocholic acid induced cholestasis. In addition, recent studies show that
CAR
activation disrupts thyroid hormone homeostasis. Finally,
CAR
activation promotes hepatocyte proliferation and blocks apoptosis, and is essential for the tumorigenesis induced by its activators PB and TCPOBOP. The role of
CAR
in endobiotic and xenobiotics metabolism has clinical implications in disease prevention, drug-drug interactions, and the development of better drug treatments.
...
PMID:CAR, the continuously advancing receptor, in drug metabolism and disease. 1610 72
Hepatocyte nuclear factor 4-alpha (HNF4alpha, NR2A1) is a nuclear receptor (NR) required for liver development and for controlling the expression of many hepatic-specific genes associated with important metabolic pathways. Many studies have also identified HNF4alpha as a direct
transactivator
of numerous xenobiotic-metabolizing cytochrome P450 (CYP) genes, suggesting that this factor is a global regulator which supports CYP transcription in the liver. Moreover, HNF4alpha expression displays a significant variability in human liver which may account for a proportion of the inter-individual variability in the expression of drug-metabolism genes and the clearance rate of a wide variety of prescribed drugs. In the last few years, a number of complex interactions and cross-talks between HNF4alpha and other transcription factors and coregulators have also surfaced, and the impact on CYP gene expression has been demonstrated. Thus, it is now clear that HNF4alpha modulates CYP expression in the liver by interacting with the xenosensor receptors (PXR and
CAR
), the glucocorticoid receptor (GR), the feeding-fasting cycle target PGC-1alpha, the sexual-dimorphism factor Stat5b, and other liver-enriched factors, such as C/EBPs. In addition to regulating drug elimination pathways, HNF4alpha also triggers pleiotropic effects on cholesterol and fatty acid metabolism, glucose homeostasis and inflammation. As a whole, current evidence indicates that HNF4alpha is a central regulator in the network of NRs that integrates drug-metabolism not only with the liver intermediate metabolism, but also with a number of patho-physiological conditions where the CYP expression is altered. The purpose of this review is to summarize and discuss these studies and their conclusions, with particular emphasis on the role of HNF4alpha in the regulation of drug-metabolizing CYP genes in the human liver.
...
PMID:Transcriptional regulation of cytochrome p450 genes by the nuclear receptor hepatocyte nuclear factor 4-alpha. 1968 47
