Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human constitutive androstane receptor (hCAR; NR1I3) is a member of the nuclear receptor superfamily. The activity of hCAR is regulated by a variety of xenobiotics including clotrimazole and acetaminophen metabolites. hCAR, in turn, regulates a number of genes responsible for xenobiotic metabolism and transport including several cytochrome P450s (CYP 2B5, 2C9, and 3A4) and the multidrug resistance-associated protein 2 (MRP2, ABCC2). Thus, hCAR is believed to be a mediator of drug-drug interactions. We identified two novel hCAR splice variants: hCAR2 encodes a receptor in which alternative splice acceptor sites are utilized resulting in a 4 amino acid insert between exons 6 and 7, and a 5 amino acid insert between 7 and 8, and hCAR3 encodes a receptor with exon 7 completely deleted resulting in a 39 amino acid deletion. Both hCAR2 and hCAR3 mRNAs are expressed in a pattern similar to the initially described MB67 (hCAR1) with some key distinctions. Although the levels of expression vary depending on the tissue examined, hCAR2 and hCAR3 contribute 6-8% of total hCAR mRNA in liver. Analysis of the activity of these variants indicates that both hCAR2 and hCAR3 lose the ability to heterodimerize with RXR and lack transactivation activity in cotransfection experiments where either full-length receptor or GAL4 DNA-binding domain/CAR ligand binding domain chimeras were utilized. Although the role of hCAR2 and hCAR3 is currently unclear, these additional splice variants may provide for increased diversity in terms of responsiveness to xenobiotics.
Mol Genet Metab
PMID:Alternative splicing within the ligand binding domain of the human constitutive androstane receptor. 1456 71

We have recently developed a replication-defective, recombinant adenovirus (Ad) vector composed of the whole Ad serotype 35 (Ad35), a member of subgroup B. We describe herein the in vitro and in vivo gene transfer properties of Ad35 vector in comparison with Ad serotype 5 (Ad5) and the Ad5F35 vector, which is a fiber-substituted Ad5 vector containing Ad35 fiber proteins. In vitro, Ad35 vector efficiently transduced not only human CAR-positive cells but also CAR-negative cells. Following intravenous administration into mice, both Ad5 and Ad35 vectors were rapidly cleared from the bloodstream with a half-life of approximately 3 min. Ad5 vector-mediated transgene expression predominantly occurred in liver parenchymal cells, although the Ad5 vector was delivered to both liver parenchymal and nonparenchymal cells. In contrast, Ad35 vector was efficiently taken up by liver nonparenchymal cells and mediated transduction efficiency in the liver on a level 4 log orders lower than the Ad5 vector. These findings demonstrate that Ad35 vector is an attractive vehicle for gene transfer into human cells, while the biodistribution profile of Ad35 vector in mice is much different from that of the Ad5 vector.
Mol Ther 2003 Nov
PMID:Characterization of in vitro and in vivo gene transfer properties of adenovirus serotype 35 vector. 1459 15

To create tumor-targeted Ad vectors, ablation of native CAR and integrin receptor binding is crucial to enhance the specificity of tumor transduction. Toward this aim, we have previously created base vectors in which binding to CAR (single-ablated) or to both CAR and integrins (double-ablated) has been ablated. In this study, the biodistribution of the conventional (CAR and integrin binding intact), single-ablated, and double-ablated vectors was evaluated following intraperitoneal administration. The mesothelial lining of the peritoneal organs was the principle site of CAR-dependent gene transfer by the conventional vector. Surprisingly, the single-ablated vector strongly transduced the liver parenchyma rather than the mesothelium, while the double-ablated vector did not significantly transduce the parenchyma or mesothelium. The high level of parenchymal transduction by the single-ablated vector suggested that it efficiently entered the bloodstream from the peritoneal cavity. Consistent with this hypothesis, a large proportion of active particles distributed and persisted in the bloodstream following intraperitoneal administration of either the single- or the double-ablated vector. The above results suggest that the double-ablated vector backbone may not only significantly improve targeting to cancers located in the peritoneal cavity, but may also significantly improve targeting to metastatic tumors located throughout the body by virtue of its enhanced bloodstream persistence.
Mol Ther 2004 Feb
PMID:Ablating CAR and integrin binding in adenovirus vectors reduces nontarget organ transduction and permits sustained bloodstream persistence following intraperitoneal administration. 1475 6

The nuclear orphan receptor CAR is active in the absence of ligand with the unique capability to be further regulated by activators. A number of these activators, including phenobarbital, do not directly bind to the receptor. Considered a xenobiotic sensing receptor, CAR transcriptionally modifies the expression of genes involved in the metabolism and elimination of xenobiotics and steroids in response to these compounds and other cellular metabolites. Its hepatic expression pattern endows the liver with the ability to protect against not only exogenous but also endogenous insults. The mechanism of CAR activation is complex, involving translocation from the cytoplasm to the nucleus in the presence of activators, followed by further activation steps in the nucleus. Although this mechanism remains under investigation, we have summarized here the cellular signaling pathways elucidated so far and speculate on the mechanism by which CAR activators regulate gene expression through this network.
Mol Endocrinol 2004 Jul
PMID:CAR, driving into the future. 1498 30

Many human tumors have a functional deficiency in p53. Numerous studies have taken advantage of this phenomenon to use a conditionally replication-competent adenovirus (Ad dl1520) that will grow in and lyse tumor cells while sparing normal tissues. However, success has been limited, in part due to difficulties in reaching a sufficiently high proportion of tumor cells. Preexisting or developing immune responses directed toward viral proteins further decrease the efficacy of the approach. We have developed a liposome-encapsulated conditionally replication-competent plasmid based on the dl1520 virus. Like the parent virus, this plasmid generates infectious particles following transfection of p53-defective, but not p53-wild-type tumor cells, but unlike the parent virus it is able to infect CAR-negative tumor cells. The antitumor efficacy of this infectious plasmid was demonstrated in mice with xenografted human tumors, in which it was active after both local and intravenous administration for subcutaneous tumors and following intravenous administration for disseminated malignancy. Activity was retained systemically, even in the presence of neutralizing antibody. Such liposomally encapsulated conditionally replication-competent plasmids may complement the use of conventional viral particles, particularly in settings in which liver uptake of adenoviral vector is undesirable or there are problematic inhibitory effects from humoral immune responses.
Mol Ther 2004 Apr
PMID:Liposomal enhancement of the antitumor activity of conditionally replication-competent adenoviral plasmids. 1509 79

Adenovirus (Ad)-mediated transduction of dendritic cells (DC) is inefficient because of the lack of the primary Ad receptor, CAR. DC infection with Ad targeted to the CD40 results in increased gene transfer. The current report describes further development of the CD40-targeting approach using an adapter molecule that bridges the fiber of the Ad5 to CD40 on mouse DC. The adapter molecule, CFm40L, consists of CAR fused to mouse CD40 ligand via a trimerization motif. A stable cell line that secretes CFm40L at high levels was generated. Gene transfer to mouse bone marrow-derived DC (mBMDC) using CFm40L-targeted Ad was over 4 orders of magnitude more efficient than that for the untargeted Ad5. Gene transfer was achieved to over 70% of the mBMDC compared to undetectable transduction using untargeted Ad5. In addition to dramatically enhanced gene transfer, the CFm40L-targeted Ad5 induced phenotypical maturation and upregulated IL-12 expression. Most importantly, the CFm40L-targeted Ad5 elicited specific immune response against a model antigen in vivo. The results of this study demonstrate that Ad-mediated gene transfer to DC can be significantly enhanced using nonnative transduction pathways, such the CD40 pathway, which may have important applications in genetic vaccination for cancer and infectious diseases.
Mol Ther 2004 May
PMID:Enhanced gene transfer to mouse dendritic cells using adenoviral vectors coated with a novel adapter molecule. 1512 Mar 32

The constitutive androstane receptor (CAR, NR1I3) is a key regulator of xenobiotic and endobiotic metabolism. The ligand-binding domains of murine (m) and human (h) CAR are divergent relative to other nuclear hormone receptors, resulting in species-specific differences in xenobiotic responses. Here we identify the widely used antiemetic meclizine (Antivert; Bonine) as both an agonist ligand for mCAR and an inverse agonist for hCAR. Meclizine increases mCAR transactivation in a dose-dependent manner. Like the mCAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, meclizine stimulates binding of steroid receptor coactivator 1 to the murine receptor in vitro. Meclizine administration to mice increases expression of CAR target genes in a CAR-dependent manner. In contrast, meclizine suppresses hCAR transactivation and inhibits the phenobarbital-induced expression of the CAR target genes, cytochrome p450 monooxygenase (CYP)2B10, CYP3A11, and CYP1A2, in primary hepatocytes derived from mice expressing hCAR, but not mCAR. The inhibitory effect of meclizine also suppresses acetaminophen-induced liver toxicity in humanized CAR mice. These results demonstrate that a single compound can induce opposite xenobiotic responses via orthologous receptors in rodents and humans.
Mol Endocrinol 2004 Oct
PMID:Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR. 1527 53

Adenoviruses are extensively studied in terms of their use as gene therapy vectors and pathogenesis. These vectors have been targeted on both transcriptional and transductional levels to achieve cell-specific gene delivery. Current detection strategies, including reporter gene expression, viral component detection, and vector labeling with fluorophores, have been applied to analyze adenoviral vectors; however, these methods are inadequate for assessing transductional targeting. As an alternative to conventional vector detection techniques, we developed a specific genetic labeling system whereby an adenoviral vector incorporates a fusion between capsid protein IX and EGFP. DNA packaging and thermostability were marginally hampered by the modification while DNA replication, cytopathic effect, and CAR-dependent binding were not affected. The fluorescent label was associated with the virus capsid and conferred a fluorescent property useful in detecting adenoviral particles in flow cytometry, tracking, and tissue sections. We believe our genetic adenovirus labeling system has important implications for vector development, detecting adenovirus vectors in targeting schemes, and studying adenovirus biology. In addition, this technique has potential utility for dynamic monitoring of adenovirus replication and spread.
Mol Imaging 2004 Apr
PMID:Fluorescently labeled adenovirus with pIX-EGFP for vector detection. 1529 75

In well-differentiated human airway epithelia, the coxsackie B and adenovirus types 2 and 5 receptor (CAR) resides on the basolateral membrane. Replacing the transmembrane and cytoplasmic tail of CAR with a glycosyl-phosphatidylinositol anchor (GPI-CAR) allows apical localization of GPI-CAR, where it can bind adenovirus and enhance gene transfer in vitro. To test this hypothesis further and to investigate requirements and barriers we developed an in vivo model that quantitatively assesses gene transfer of erythropoietin (EPO) to mouse airway epithelia. Our data suggest that erythropoietin is secreted basolaterally, allowing possible access to the bloodstream. The data also suggest that basolateral adenovirus-mediated airway epithelia EPO secretion persists for long periods and could be used to study persistence in vivo. Additionally, the increase in hematocrit in response to the increased serum EPO could be used for therapeutic purposes. Finally, we tested the ability of apically localized CAR to enhance the infection of AdEPO in mouse airway epithelia in vivo. The data suggest that apical receptors in airway epithelia may be sufficient to improve adenovirus infection of airway epithelia in vivo.
Mol Ther 2004 Sep
PMID:Adenovirus-mediated erythropoietin production by airway epithelia is enhanced by apical localization of the coxsackie-adenovirus receptor in vivo. 1533 50

The nuclear receptors CAR and PXR activate hepatic genes in response to therapeutic drugs and xenobiotics, leading to the induction of drug-metabolizing enzymes, such as cytochrome P450. Insulin inhibits the ability of FOXO1 to express genes encoding gluconeogenic enzymes. Induction by drugs is known to be decreased by insulin, whereas gluconeogenic activity is often repressed by treatment with certain drugs, such as phenobarbital (PB). Performing cell-based transfection assays with drug-responsive and insulin-responsive enhancers, glutathione S-transferase pull down, RNA interference (RNAi), and mouse primary hepatocytes, we examined the molecular mechanism by which nuclear receptors and FOXO1 could coordinately regulate both enzyme pathways. FOXO1 was found to be a coactivator to CAR- and PXR-mediated transcription. In contrast, CAR and PXR, acting as corepressors, downregulated FOXO1-mediated transcription in the presence of their activators, such as 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and pregnenolone 16alpha-carbonitrile, respectively. A constitutively active mutant of the insulin-responsive protein kinase Akt, but not the kinase-negative mutant, effectively blocked FOXO1 activity in cell-based assays. Thus, insulin could repress the receptors by activating the Akt-FOXO1 signal, whereas drugs could interfere with FOXO1-mediated transcription by activating CAR and/or PXR. Treatment with TCPOBOP or PB decreased the levels of phosphoenolpyruvate carboxykinase 1 mRNA in mice but not in Car(-/-) mice. We conclude that FOXO1 and the nuclear receptors reciprocally coregulate their target genes, modulating both drug metabolism and gluconeogenesis.
Mol Cell Biol 2004 Sep
PMID:Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. 1534 55


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