Journal.hep.com.cn

Protein Cell 2014, 5(2):113–123DOI 10.1007/s13238-013-0013-0 Signaling control of the constitutiveandrostane receptor (CAR) Hui Yang, Hongbing Wang& Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201,USA& Correspondence: hwang@rx.umaryland.edu (H. Wang)Received November 24, 2013 Accepted December 7, 2013 ; Plant, Originally cloned as a constitutively activated receptor without a clearly defined biological func- The constitutive androstane receptor (CAR, NR1I3) plays tion, the importance of CAR in xenobiotic metabolism was a crucial role in the regulation of drug metabolism, first appreciated when CAR was functionally linked to the energy homeostasis, and cancer development through long-known phenobarbital-mediated induction of hepatic modulating the transcription of its numerous target cytochrome P450 (CYP) 2B gene family (Honkakoski et al., genes. Different from prototypical nuclear receptors, ; Kawamoto et al., Encouraged by these find- CAR can be activated by either direct ligand binding or ings, numerous investigations have been carried out to ligand-independent (indirect) mechanisms both initiated explore the role of CAR in xenobiotic metabolism, detoxifi- with nuclear translocation of CAR from the cytoplasm. In cation, and clearance (Maglich et al., ; Tolson and comparison to the well-defined ligand-based activation, Wang, ). In humans, two functional enhancer modules, indirect activation of CAR appears to be exclusively namely the phenobarbital-responsive enhancer module involved in the nuclear translocation through mecha- (PBREM) and the xenobiotic-responsive enhancer module nisms yet to be fully understood. Accumulating evi- (XREM), have been identified upstream of the CYP2B6 gene dence reveals that without activation, CAR forms a and functionally characterized as the CAR binding sites in protein complex in the cytoplasm where it can be func- response to chemical stimuli (Honkakoski et al., Wang tionally affected by multiple signaling pathways. In this et al., CAR is also known to control the inductive review, we discuss recent progresses in our under- expression of other CYP enzymes such as CYP3A4 standing of the signaling regulation of CAR nuclear (Goodwin et al., ), CYP2Cs (Ferguson et al., accumulation and activation. We expect that this review Gerbal-Chaloin et al., ), CYP2A6 (Wortham et al., will also provide greater insight into the similarity and ), and to a lesser extent CYP1A1 and CYP1A2 (Yosh- difference between the mechanisms of direct vs. indirect inari et al., which contribute to the metabolism of human CAR activation.
approximately 75% of clinically used drugs and the detoxi-fication of numerous environmental chemicals (Johansson constitutive androstane receptor, nuclear and Ingelman-Sundberg, ). Further studies have translocation, phosphorylation, signaling regulation extended CAR target genes including those encoding phaseII enzymes such as the uridine diphosphate glucuronosyl-transferase (UGT) isoforms (i.e., UGT1A1, UGT1A6, and UGT1A9) (Sugatani et al., Osabe et al., ; Buckley The constitutive androstane receptor (CAR), a member of and Klaassen, glutathione S-transferases and sul- the nuclear receptor superfamily (subfamily 1, group I, fotransferases (Maglich et al., Yanagiba et al., ), member 3 [NR1i3]), plays an important role in coordinating as well as efflux and uptake drug transporters such as cellular responses to the stimulation of both exogenous and multidrug resistance-associated proteins (MRPs) (Cherring- endogenous chemicals by regulating the expression of its ton et al., ), multidrug resistance protein 1 target genes (Qatanani and Moore, Stanley et al., (MDR1) (Burk et al., ; Cerveny et al., ), The Author(s) 2014. This article is published with open access at Springerlink.com and journal.hep.com.cn Hui Yang and Hongbing Wang and organic anion-transporting polypeptide 1 (OATP1) (Ding illustrating an anti-cancer potential (Chakraborty et al., et al., Osabe et al., ). In addition to its broad ). Moreover, the enhanced cell proliferation by pheno- spectrum of target genes, CAR also senses numerous barbital in the liver of wild-type mice was completely abro- xenobiotics and endobiotics as activators or deactivators gated in the double-humanized CAR and pregnane X receptor (PXR) mouse model (Ross et al., Although metabolism, detoxification, and clearance in the liver. Up- the underlying mechanisms of the significant species differ- regulation of these drug-metabolizing enzymes or drug ences of CAR in tumor development are largely unknown, transporters by CAR activators may accelerate the bio- such variances might be attributed to the divergent regula- transformation of co-administered drugs, usually leading to tion of differential genes governing DNA synthesis, cell efficacy, enhanced toxicity, or proliferation, apoptosis, and migration by hCAR vs. its rodent increased bioactivation of prodrugs. For instance, recent counterparts (Ross et al., Kamino et al., Tak- studies in our lab have demonstrated that activation of CAR izawa et al., Collectively, findings from these initial can enhance the bioactivation of cyclophosphamide (CPA) basic investigations hold the potential to advance CAR from and facilitate CPA-based chemotherapeutic activity in leu- a well-known xenobiotic sensor to an endobiotic modulator kemia cells (Wang et al., ). Understanding the role of that may eventually become a promising drug target for CAR in mediating variable drug responsiveness and drug- metabolic disorders as well as cancer therapy.
drug interactions has become an intense focus of both Unlike PXR, the closest relative of CAR in the nuclear academic and industrial research efforts and may lead to receptor superfamily tree, CAR is constitutively activated in enhanced prediction of drug-drug interactions and xenobi- nearly all immortalized cells and spontaneously accumulated in nuclei of these cells prior to chemical stimulated activation Other than the well-established roles of CAR in the reg- (Kawamoto et al., ). Moreover, CAR is featured as a ulation of drug metabolism and transport, where it functions nuclear receptor that could be transactivated through either as a xenobiotic sensor, emerging evidence strongly sug- the classical direct ligand binding or a mutedly defined gests that CAR also modulates various hepatic functions that ligand-independent indirect mechanism (Kawamoto et al., control diverse physiological and pathophysiological condi- ; Maglich et al., ). These characteristics make the tions, including energy metabolism, insulin signaling, cell studies of CAR activation extremely challenging and pose proliferation, and tumor development (Fig. ). In mice, major difficulties for evaluating drug-mediated CAR activa- selective activation of CAR significantly alleviated high fat tion in vitro. This review is aimed to highlight the recent diet-induced obesity and type 2 diabetics via a combined advances in our understanding of the molecular mecha- inhibition of lipogenesis, fatty acid synthesis, and gluco- nisms behind drug-mediated nuclear translocation and acti- neogenesis, as well as the increase of energy expenditure in vation of CAR, with a particular focus centered on signaling brown adipose tissues (Dong et al., Gao et al., pathways that contribute to indirect activation of CAR.
Masuyama and Hiramatsu, Particularly, CAR influ-ences energy homeostasis by suppressing the expression of ACTIVATION OF CAR phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) (Kachaylo et al., sterol regu- As a so-called orphan receptor, CAR can be activated by a latory element-binding protein 1c (Roth et al., ), acetyl- broad array of xenobiotic chemicals, often at micromolar CoA carboxylase 1, fatty acid synthase (FAS), and stearoyl- concentrations, which differs from the classical steroid-hor- CoA desaturase-1 (SCD-1) (Du et al., ). The essential mone receptors which respond to endogenous ligands at role of CAR in phenobarbital- and 1,4-bis[2-(3,5-dichloro- nanomolar concentrations (Giguere, Tzameli and pyridyloxy)] benzene (TCPOBOP)-induced tumor promotion Moore, ). Structurally, however, CAR shares common was initially established by using CAR knockout and wild- functional features with other typical nuclear receptors, type mice (Yamamoto et al., Huang et al., In including a highly variable N-terminal AF1 domain, a DNA this regard, the known tumor promoters stimulated cancer binding domain (DBD), a ligand-binding domain (LBD), and a progression by a CAR-dependent perturbation of the C-terminal AF2 domain. The highly conserved DBD contains expression of the growth arrest and DNA damage-inducible unique structures that can recognize and bind to specific 45 beta (GADD45B) (Columbano et al., ), the murine promoter regions in target genes, namely xenobiotic double minute 2 (mdm2) (Huang et al., as well as the response elements such as the aforementioned PBREM and newly identified tubulin alpha 8 (TUBA8) (Kamino et al., XREM in the CYP2B6 promoter. Response elements binding In contrast to these observed roles of murine CAR in to CAR are usually composed of two direct repeats of the tumor development, activation of human (h) CAR by the consensus hexametric sequence of AG(G/T)TCA spaced by three to four nucleotides (i.e., DR3 or DR4) (Makinen et al., ). In the nucleus, CAR only binds to its response ele- CO), appears to be associated with cell cycle arrest and ments after forming heterodimers with the retinoid X receptor enhanced apoptosis in human brain tumor stem cells, (RXR). The X-ray crystal structure of the hCAR/RXR LBDs The Author(s) 2014. This article is published with open access at Springerlink.com and journal.hep.com.cn Signaling control of CAR PhaseI/II enzymes Drug transporters (SREBP, ACC, FAS) Cell proliferation Figure 1. Schematic illustration of biological functions of CAR. The size of hollow arrows indicates the abundance of available evidence for each function of CAR. Up and down black arrows symbolize increased and decreased gene expression, respectively.
reveals that CAR contains a single-turn Helix X that restricts that TCPOBOP dose-dependently restores mCAR activity the conformational freedom of the C-terminal AF2, and a following inhibition by the inverse agonists (Tzameli et al., relatively small ligand binding pocket (Xu et al., ). Such ). Notably, mutation of key residues inside the mCAR features permit CAR to interact with co-activator proteins and ligand-binding pocket entirely eliminated the stimulatory maintain a constitutively activated status once translocated effect of TCPOBOP, as well as the inhibitory effect of an- into the nucleus. Importantly, although CAR shares several drostanes, without affecting the constitutive activity of CAR common characteristics with classical nuclear receptors, (Tzameli et al., ). These results clearly establish CAR increasing evidence suggests that CAR can be activated by as a xenobiotic responsive modular protein that can be both direct ligand-binding and ligand-independent mecha- activated/deactivated by binding with agonistic and antago- nisms (Kawamoto et al., Maglich et al., ). To this nistic ligands, respectively.
end, it appears that CAR activation is a multi-step process Importantly, CAR exhibits remarkable species selectivity and most identified CAR activators may not directly bind to in its ligand binding and activation profiles, which makes the receptor.
direct extrapolation of findings from mouse to human extre-mely risky. For example, TCPOBOP and estradiol activatemouse but not human CAR, and pharmacological concen- Direct activation trations of androstanol, progesterone, and testosterone Owing to the constitutive activation of CAR, the initial search repress mouse but not human CAR (Handschin and Meyer, for CAR ligands has resulted with the identification of andr- ; Maglich et al., The first selective hCAR agonist, ostenol and androstanol as inverse-agonists of CAR (For- the imidazothiazole derivative-CITCO, came through a man et al., Mechanistically, these androstanes combination of in vitro and cell-based screening in 2003 convert CAR from constitutive to basal activity by disrupting (Maglich et al., ). CITCO selectively binds to hCAR and the salt bridge that locks the H12 helix in its active confor- activates CAR target genes in human primary hepatocytes mation, promoting co-activator release from the LBD without (Maglich et al., ; Ferguson et al., ; Faucette et al., interfering CAR/RXR dimerization or DNA binding (Shan ). Recent evidence also reveals that CITCO can effi- et al., Subsequent studies uncovered TCPOBOP, the ciently enhance recruitment of co-activators to the LBD of most potent known member of the phenobarbital-like class of hCAR by competing with antagonists such as PK11195 (Li CYP2B inducers, as the first agonist of mouse (m) CAR, in et al., and metformin (Yang et al., However, The Author(s) 2014. This article is published with open access at Springerlink.com and journal.hep.com.cn Hui Yang and Hongbing Wang CITCO only moderately enhances the constitutively acti- major breakthrough came with the identification of the con- vated hCAR (less than 2-fold), compared with that of served threonine (Thr)-38 of human CAR as the primary TCPOBOP for mCAR (5- to 10-fold) in cell-based luciferase residue that governs nuclear translocation and activation of reporter assays (Tzameli et al., ; Maglich et al., CAR (Mutoh et al., Dephosphorylation of the Thr-38 Moreover, CITCO also activates human PXR and induces appears to be essential for CAR translocation regardless of PXR target genes at higher concentrations, leaving direct exposure to direct or indirect activators (Mutoh et al., ).
comparison of human CAR and PXR target genes yet The exact molecular mechanisms controlling Thr-38 CAR challenging (Maglich et al., ). To date, there is no pure hCAR agonist reported. Other chemicals exhibiting agonistic understood. However, several kinase signaling pathways effects on hCAR such as the antimalarial artemisinin, the have recently been suggested to be important in the phos- psychoactive diazepam and the anti-fungal myclobutani, are phorylation of CAR.
also associated with potent activation of hPXR (Burk et al.,Li et al., ). Overall, ligand-dependent direct Protein phosphatase 2A (PP2A) activation of CAR may still rely on its initial step of translo- The role of protein kinase-based signaling pathways in cating CAR into the nucleus. Once inside the nucleus, CIT- controlling phenobarbital-mediated induction of CYP450s CO bound hCAR adopts a conformation similar to the had been proposed, even before CAR was recognized as constitutively active apo-CAR and maintains the intrinsically the fundamental target of phenobarbital. Early studies high consititutive activity.
showed that both activation of protein kinase A (PKA) by elevated intracellular cyclic adenosine monophosphate Indirect activation (cAMP) and the inhibition of protein phosphatases PP1 and The hallmark feature that differentiates CAR from classical PP2A by okadaic acid (OA) resulted in complete repression nuclear receptors lies in its ligand-independent nuclear of phenobarbital-inducible CYP gene transactivation in pri- accumulation and constitutive activation once expressed mary rat hepatocytes (Sidhu and Omiecinski, ).
inside the nucleus of cells. To date, numerous CAR activa- Although the transcription factor(s) that drive the phenobar- tors have been identified, including clinically used drugs, bital induction event was/were yet to be determined, these environmental chemicals, and endogenous steroid metabo- results indicated that both PKA and protein phosphatase lites (Qatanani and Moore, Li and Wang, Molnar pathways exert marked roles in modulating the signaling of et al., Most of these activators however do not bind phenobarbital-mediated CYP induction. After establishing directly to CAR; instead activating CAR by stimulating its CAR as the critical DNA-binding protein required for phe- nuclear translocation in a ligand-independent manner (Li nobarbital response, Negishi and colleagues demonstrated et al., For example, the typical CYP2B inducer and that OA pretreatment was sufficient to inhibit phenobarbital- CAR activator phenobarbital does not bind directly to CAR mediated nuclear translocation of CAR and induction of but induces CAR transcriptional activition exclusively via Cyp2b10 in primary mouse hepatocytes, suggesting that nuclear translocation (Kawamoto et al., Moore et al., CAR nuclear accumulation is most likely regulated by a ). Notably, constitutive activation of CAR is not always a dephosphorylation-sensitive signaling cascade (Kawamoto beneficial feature. In this regard, CAR activation can et al., Further studies from the same research group enhance the metabolism and toxicity of some drugs, such as revealed that CAR exists as a complex with Hsp90 in the acetaminophen (Zhang et al., ), and potentially increase cytoplasm of non-induced mouse liver hepatocytes. More tumor propensity by stimulating cell proliferation (Takizawa importantly, phenobarbital treatment recruited PP2A to the et al., ). To accommodate such potential adversity, CAR protein complex, which led to the dephosphorylation of CAR is primarily located in the cytoplasm prior to activation in (Yoshinari et al., ).
primary hepatocytes and intact liver in vivo (Kawamoto et al., Realizing the importance of phosphorylation/depho- ; Li et al., ). In this native hepatocyte environment, sphorylation in CAR nuclear translocation and activation, the CAR is spontaneously sequestered in the cytoplasm as a next significant question to be answered was which amino multi-protein complex including the heat shock protein 90 acid residue(s) is/are responsible for such chemical-stimu- (Hsp90), cytoplasmic CAR retention protein, protein phos- lated signaling. Serial-deletion and site-directed mutagene- phatase 1 regulatory subunit 16A, and potentially other yet sis of CAR led to the identification of a leucine-rich motif unidentified proteins (Kobayashi et al., ; Yoshinari et al., (LXXLXXL) close to the C-terminal region, namely the ; Sueyoshi et al., Upon the stimulation of phe- xenobiotic response sequence (XRS), as the potential nobarbital-type indirect activators or CITCO/TCPOBOP-like functional unit which dictates the nuclear translocation of direct ligand-binding, CAR disassociates from the cytoplas- CAR in response to various phenobarbital-type inducers mic localized protein complex and moves into the nucleus. It (Zelko et al., Xia and Kemper, ). Nevertheless, was believed that this process is regulated by protein kinase- these residues were not direct targets of either PP2A or mediated phosphorylation/dephosphorylation of CAR. A PKA. A real breakthrough in this regard came with the The Author(s) 2014. This article is published with open access at Springerlink.com and journal.hep.com.cn Signaling control of CAR diligent work by Mutoh et al. in 2009, in which the Thr-38 phenobarbital-mediated induction of CYP2B1 was stimu- residue of hCAR was established as the primary determinant lated in the liver of diabetic rats where p38 MAPK was for chemical-mediated phosphorylation/ dephosphorylation activated by the disease itself (Yoshida et al., while of CAR, while dephosphorylation of Thr-38 is a prerequisite CYP induction by phenobarbital was attenuated in tumor- for CAR translocation into the nucleus (Mutoh et al., bearing rats where p38 MAPK was down-regulated (Nu- Consistent with earlier observations, treatment with OA mazawa et al., Nonetheless, a definite role of p38 increased the phosphorylation of CAR at Thr-38 and MAPK in CAR activation has yet to be established, given that sequestered CAR in the cytoplasm of mouse primary activation of p38 MAPK appears to enhance some but not all hepatocytes (Mutoh et al., ).
target genes of hCAR.
Epidermal growth factor receptor (EGFR) Extracellular signal-regulated kinase (ERK) and p38mitogen-activated protein kinase (MAPK) Previous studies have shown that phenobarbital-inducedCYP2B gene transactivation could be effectively repressed Accumulating evidence has demonstrated that expression of by growth factors, such as EGF and insulin-like growth factor various CYP enzymes was significantly repressed during (IGF) (Bauer et al., Kietzmann et al., ; Thasler liver regeneration, infection or inflammation, suggesting et al., ). EGFR is a member of the ErbB family of cellular signaling molecules such as growth hormones and receptors that coordinates extracellular signals, such as cytokines may play a role in the expression of xenobiotic- EGF, to cellular signaling cascades and eventually promotes metabolizing CYPs (Bauer et al., Koike et al., ). In cell proliferation (Di Fiore et al., Recent studies by particular, two independent studies provided strong evidence Mutoh et al., identified EGFR as a phenobarbital-responsive to show that phenobarbital-dependent activation of the rat receptor that mediates CAR dephosphorylation and activa- CYP2B1 promoter was repressed by the presence of epi- tion in mouse primary hepatocytes (Mutoh et al., As dermal growth factor (EGF) but promoted by U0126, a shown in this study, phenobarbital antagonizes EGF-stimu- known inhibitor of the MEK-ERK signaling pathway (Bauer lated EGFR phosphorylation and activation; abrogation of et al., Joannard et al., ). Encouraged by these EGFR signaling further induces the dephosphorylation of the observations, Negishi and coworkers provided further downstream receptor for activated C kinase 1 (RACK1) at mechanistic evidence suggesting ERK is an endogenous the residue of Tyr-52. The dephosphorylated RACK1 then signal, regulating CAR phosphorylation and nuclear trans- directly recruits PP2A to the cytosol localized CAR protein location, by which U0126-mediated Cyp2b10 induction via complex, where it dephosphorylates and releases CAR into ERK1/2 deactivation was completely abrogated in CAR the nucleus (Fig. More importantly, this study provides the knockout mice (Koike et al., Moreover, co-immuno- first evidence that phenobarbital can directly bind to EGFR at precipitation experiments revealed that activated ERK1/2 co- pharmacologically relevant concentrations. Given that phe- precipitated only with the Thr-38 phosphorylated CAR, nobarbital is often referred to as an "orphan compound" where the C-terminal located XRS appears to be essential without a known direct target, EGFR may represent one of for this interaction (Osabe and Negishi, This interac- the molecular targets that initiates phenobarbital-mediated tion was significantly increased after EGF exposure while cellular responses, including CAR activation. On the other treatment with U0126 decreased the level of CAR phos- hand, phenobarbital may not function as a prototypical phorylation at Thr-38 and eventually released CAR into the EGFR inhibitor, such as gefitinib and erlotinib, which can nucleus (Osabe and Negishi, ).
antagonize EGFR-mediated cell proliferation and tumor An outstanding phenomenon observed was that ectopic development (Nakajima et al., ; Shin et al., ). In expression of hCAR in HepG2 cells does not convey optimal fact, phenobarbital itself is a potent tumor promoter in rodent induction of CYP2B6 compared to what was observed in animals via a CAR-dependent mechanism (Huang et al., human primary hepatocytes; many other cellular signals ; Yamamoto et al., ). Therefore, it is reasonable to have been shown to regulate the activation of CAR.
speculate that phenobarbital might be an atypical antagonist Recently, the p38 MAPK was identified as a required factor of EGFR, which only selectively inhibits certain downstream optimizing CAR activation and CYP2B6 induction in liver events of EGFR signaling.
cells (Saito et al., ). In human primary hepatocytes, p38MAPK is highly activated, which significantly differs from that AMP activated protein kinase (AMPK) in human hepatoma cell lines, including HepG2 cells. Acti-vation of p38 MAPK by anisomycin robustly potentiated AMPK is an enzyme that functions as an energy sensor by induction of CYP2B6 mRNA by CAR activators in HepG2 regulating cellular energy metabolism and homeostasis.
cells to levels that were comparable to what was observed in AMPK plays an important role in fatty acid oxidation, glucose ligand-treated human primary hepatocytes. The potential uptake, and hepatic lipogenesis by reacting to the fluctuation significance of p38 MAPK in chemical-elicited CAR activa- of the cellular AMP:ATP ratio (Hardie et al., Inoki et al., tion was also indirectly supported by the facts that ). Recent studies suggested that AMPK is involved in The Author(s) 2014. This article is published with open access at Springerlink.com and journal.hep.com.cn Hui Yang and Hongbing Wang Collectively, these studies implicate rather contradictory outcomes when connecting CYP2B transactivation and CAR nuclear translocation to AMPK activation. Some of the dis-putes however, can be explained at least in part by the diverse physiological properties of different species or cell systems used in these studies, such as immortalized celllines vs. primary hepatocytes, human cells vs. rodent cells,and in vivo vs. in vitro. In addition, energy status and nutri-tional environment of the cells can also influence pheno- barbital regulation of the CYP2B gene (Yoshida et al., Figure 2. Antagonistic effect of phenobarbital on EGFR Rencurel et al., signaling and CAR activation. Arrows indicate activation and the blunt arrow represents deactivation. (This figure was Transcriptional regulation of CAR adopted from Mutoh et al., Science Signaling).
Although the biological function of CAR relies predominantly CAR-regulated CYP2B gene induction by phenobarbital- on chemical-mediated activation/deactivation through direct type inducers, but the precise role of AMPK in the activation or indirect mechanisms, the expression level of CAR in of CAR remains controversial. Studies from Meyer and col- response to endogenous signals or xenobiotic chemicals leagues showed that AMPK activator 5-AMINO-1-β-Dffff- may also influence the downstream regulation of its target ribofuranosyl-imidazole-4-carboxamide (AICAR), or expres- genes. It is well known that dramatic interindividual differ- sion of a constitutively active form of AMPK, mimicked ences exist in the expression of hepatic CYP2B6, the pro- phenobarbital-mediated induction of CYP2B6 in hepatoma totypical target gene of hCAR (Wang and Tompkins, ).
cell lines (Rencurel et al., On the other hand, liver- Nevertheless, the molecular mechanism(s) underlying this specific deletion of AMPK catalytic subunits in mice impaired large variability remains elusive. In comparison of a panel of the inductive expression of Cyp2b10 and Cyp3a11, but did 12 individual human liver samples, Chang et al. revealed that not inhibit the nuclear accumulation of CAR induced by substantial interindividual differences of hCAR expression in phenobarbital (Rencurel et al., ). Therefore, the authors these samples were significantly and positively correlated presumed the existence of another control step of CAR with that of CYP2B6, indicating the abundance of this tran- signaling independent of translocation. However, an in vivo scription factor may contribute to the varied expression of the study conversely showed that AICAR and metformin induced CYP2B6 gene in human liver (Chang et al., ). Other CAR nuclear translocation but failed to induce hepatic studies highlighted that different from cognate CAR activa- CYP2B genes in mice and rats, suggesting AMPK activation tion, expression of CAR can be induced by a number of is not sufficient for CYP2B induction (Shindo et al., xenobiotics including the glucocorticoid receptor agonist In another study, AICAR was shown to prevent nuclear (dexamethasone) (Pascussi et al., and peroxisome translocation of CAR and repress phenobarbital-induced CYP2B expression in rat primary hepatocytes (Kanno et al., (WY14643 and ciprofibrate) (Saito et al., ). In silico ). In the same study, metformin and the constitutively analysis of the human CAR 5′-regulatory region led to the active form of AMPK, however, enhanced PBREM-driven identification of a putative glucocorticoid responsive element transactivation by phenobarbital, suggesting AICAR inhibits located between -4477 and -4410 base pair (Pascussi et al., CAR translocation in an AMPK-independent manner. Most ), a functional PPAR-alpha responsive element around recently, we have shown that metformin dramatically -4400 base pair, as well as a conserved hepatocyte nuclear repressed phenobarbital/CITCO-induced CYP2B6 expres- factor 4 alpha (HNF4α) binding site from upstream of the sion through inhibiting dephosphorylation and nuclear transcriptional start site (Ding et al., translocation of CAR (Yang et al., Consistent with this Previous animal studies have demonstrated that fasting observation, our data also demonstrated that AICAR mim- and caloric restriction increase the expression and activity icked the effect of metformin on CYP2B6 suppression, and of CAR which in turn coordinates an adaptive response by such repression was partially but concentration-dependently slowing down the energy expenditure. CAR knockout ani- restored by co-treatment with compound C (6-[4-(2-piperidin- mals were unable to couple the metabolic adjustment and lost more weight (Maglich et al., Qatanani et al., dine, a known inhibitor of AMPK. Although sequence align- ). Given that fasting typically increases the plasma ments of the conserved Thr-38 region of CAR revealed no level of free fatty acids that are natural ligands of PPARα, consensus AMPK site, signaling molecules downstream of and elevated interaction between PGC-1α and HNF4α is a the AMPK pathway such as PKC (He et al., ) may hallmark of fasting adaptation, functionally establishing CAR function as the switch controlling CAR phosphorylation and as a target gene of PPARα and HNF4α provides a novel its disassociation from the retaining protein complex.
mechanistic model for CAR in energy homeostasis (Ding The Author(s) 2014. This article is published with open access at Springerlink.com and journal.hep.com.cn Signaling control of CAR EGF, Phenobarbital Figure 3. Signaling control of CAR activation. Chemicals illustrating activation or deactivation of a signaling pathway are denoted in blue and red, respectively.
et al., ). Additional evidence indicated that stress-acti- transcription of genes associated with drug metabolism and vated protein kinase and ERK signaling pathways are also transport, energy homeostasis, and cell proliferation. Our associated with altered expression of CAR under serum- understanding of the role of CAR in gene regulation as well as starvation stress (Osabe et al., Most recently, our the mechanisms of its activation has increased remarkably own data have unexpectedly revealed that an insulin-like during the past 15 years. As summarized in this review, an growth factor-1 receptor (IGF-1R) inhibitor (BMS-665351) astonishing number of cellular factors and foreign compounds significantly induced the expression of CYP3A4 in human intertwine in the regulation of CAR biological functions.
primary hepatocytes without activation of either CAR or Although CAR shares several common features with its sister PXR, instead it selectively induced the expression of CAR receptor PXR, where they overlap in a number of target genes (Li et al., ). Intriguingly, BMS-665351 did not activate and xenobiotic activators, the mechanisms of CAR activation either glucocorticoid receptor or PPARα at concentrations have been proven to be relatively unique. To date, mounting that induced the expression of CYP3A4 and CAR, implying evidence demonstrates that CAR can be activated through additional, yet unknown mechanisms may be involved in the both classical ligand binding and ligand-independent mech- transcriptional regulation of CAR. Collectively, in compari- anisms, with indirect activation appearing to be predominant.
son with the heightened focus on the activation and deac- Seminal works by Negishi and colleagues have shown that tivation of CAR, much less is known regarding how the the phosphorylation status of CAR is pivotal for its cellular expression of CAR itself is controlled under the challenge of localization and activation, which could be influenced by many both endogenous and xenobiotic chemicals. Clearly, tran- protein kinase signals (Mutoh et al., ). In the meantime, scriptional regulation of the regulator would represent the cellular expression of CAR itself appears to be affected by another layer of CAR biology.
certain signaling molecules. Together, these data indicate thatCAR may represent a cell signaling-regulated nuclearreceptor rather than a typical ligand-dependent nuclear CONCLUDING REMARKS receptor (Fig. ). Given that CAR can be activated both It is evident now that CAR has evolved into a sensor of both directly and indirectly, it is essential to keep in mind that the xenobiotic and endobiotic chemicals by governing the ligand binding and kinase signaling may interconnect to The Author(s) 2014. This article is published with open access at Springerlink.com and journal.hep.com.cn Hui Yang and Hongbing Wang achieve the optimal activation of this receptor. Undoubtedly, Burk O, Arnold KA, Geick A, Tegude H, Eichelbaum M (2005a) A better understanding of the signaling control of CAR activation role for constitutive androstane receptor in the regulation of will eventually benefit the prediction of metabolism-based human intestinal MDR1 expression. Biol Chem 386:503–513 drug exposure as well as the development of CAR modulators Burk O, Arnold KA, Nussler AK, Schaeffeler E, Efimova E, Avery BA, as potential drug candidates.
Avery MA, Fromm MF, Eichelbaum M (2005b) Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expres- sion by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol 67:1954–1965 The authors are grateful to members of the Wang laboratory for Cerveny L, Svecova L, Anzenbacherova E, Vrzal R, Staud F, Dvorak discussions and comments on the paper, in particular, to Caitlin Z, Ulrichova J, Anzenbacher P, Pavek P (2007) Valproic acid Lynch, Brandy Garzel, and William Hedrich for their critical reading induces CYP3A4 and MDR1 gene expression by activation of of the manuscript. We apologize to the scientists who made contri- constitutive androstane receptor and pregnane X receptor path- butions to the field, but have not been cited due to space limitations.
ways. Drug Metab Dispos 35:1032–1041 This work was supported by NIH grants DK061652 and GM107058.
Chakraborty S, Kanakasabai S, Bright JJ (2011) Constitutive androstane receptor agonist CITCO inhibits growth and expan- sion of brain tumour stem cells. Br J Cancer 104:448–459 Chang TK, Bandiera SM, Chen J (2003) Constitutive androstane AMPK, AMP activated protein kinase; cAMP, cyclic andenosine receptor and pregnane X receptor gene expression in human monophosphate; CAR, constitutive androstane receptor; CITCO, 6- liver: interindividual variability and correlation with CYP2B6 mRNA levels. Drug Metab Dispos 31:7–10 dichlorobenzyl)oxime; EGF, epidermal growth factor; EGFR, EGF Cherrington NJ, Hartley DP, Li N, Johnson DR, Klaassen CD (2002) receptor; EGR1, early growth response 1; ERK, extracellular signal Organ distribution of multidrug resistance proteins 1, 2, and 3 regulated kinase; GRIP1, glucocorticoid receptor-interacting protein (Mrp1, 2, and 3) mRNA and hepatic induction of Mrp3 by 1; HNF4α, hepatocyte-enriched nuclear receptor 4 alpha; HSP90, constitutive androstane receptor activators in rats. J Pharmacol heat shock protein 90; MAPK, mitogen-activated protein kinase; OA, Exp Ther 300:97–104 okadaic acid; PBREM, phenobarbital-responsive enhancer module; Cherrington NJ, Slitt AL, Maher JM, Zhang XX, Zhang J, Huang W, Wan YJ, Moore DD, Klaassen CD (2003) Induction of multidrug coactivator-1 alpha; PKA, protein kinase A; PP2A, protein phos- resistance protein 3 (mrp3) in vivo is independent of constitutive phatases 2A; PXR, pregnane X receptor; RACK1, receptor for acti- androstane receptor. Drug Metab Dispos 31:1315–1319 vated C kinase 1; RXR, retinoid X receptor; SRC1, steroid receptor Columbano A, Ledda-Columbano GM, Pibiri M, Cossu C, Men- egazzi M, Moore DD, Huang W, Tian J, Locker J (2005) Gadd45beta is induced through a CAR-dependent, TNF-inde- XREM, xenobiotic-responsive enhancer module.
pendent pathway in murine liver hyperplasia. Hepatology COMPLIANCE WITH ETHICS GUIDELINES Di Fiore PP, Segatto O, Taylor WG, Aaronson SA, Pierce JH (1990) EGF receptor and erbB-2 tyrosine kinase domains confer cell Hui Yang and Hongbing Wang declare that they have no conflict of specificity for mitogenic signaling. Science 248:79–83 Ding X, Lichti K, Kim I, Gonzalez FJ, Staudinger JL (2006) Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma This article is distributed under the terms of the Creative Commons coactivator-1 alpha. J Biol Chem 281:26540–26551 Attribution License which permits any use, distribution, and Dong B, Saha PK, Huang W, Chen W, Abu-Elheiga LA, Wakil SJ, reproduction in any medium, provided the original author(s) and Stevens RD, Ilkayeva O, Newgard CB, Chan L et al (2009) the source are credited.
Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc Natl Acad Sci USA 106:18831–18836 Du J, Chen Q, Takemori H, Xu H (2008) SIK2 can be activated by Bauer D, Wolfram N, Kahl GF, Hirsch-Ernst KI (2004) Transcriptional deprivation of nutrition and it inhibits expression of lipogenic regulation of CYP2B1 induction in primary rat hepatocyte genes in adipocytes. Obesity (Silver Spring) 16:531–538 cultures: repression by epidermal growth factor is mediated via Faucette SR, Sueyoshi T, Smith CM, Negishi M, Lecluyse EL, Wang a distal enhancer region. Mol Pharmacol 65:172–180 H (2006) Differential regulation of hepatic CYP2B6 and CYP3A4 Buckley DB, Klaassen CD (2009) Induction of mouse UDP- genes by constitutive androstane receptor but not pregnane X glucuronosyltransferase mRNA expression in liver and intestine receptor. J Pharmacol Exp Ther 317:1200–1209 by activators of aryl-hydrocarbon receptor, constitutive andro- Ferguson SS, LeCluyse EL, Negishi M, Goldstein JA (2002) stane receptor, pregnane X receptor, peroxisome proliferator- Regulation of human CYP2C9 by the constitutive androstane activated receptor alpha, and nuclear factor erythroid 2-related receptor: discovery of a new distal binding site. Mol Pharmacol factor 2. Drug Metab Dispos 37:847–856 The Author(s) 2014. This article is published with open access at Springerlink.com and journal.hep.com.cn Signaling control of CAR Ferguson SS, Chen Y, LeCluyse EL, Negishi M, Goldstein JA (2005) Kanno Y, Inoue Y, Inouye Y (2010) 5-aminoimidazole-4-carboxa- Human CYP2C8 is transcriptionally regulated by the nuclear mide-1-beta-ribofuranoside (AICAR) prevents nuclear transloca- receptors constitutive androstane receptor, pregnane X receptor, tion of constitutive androstane receptor by AMP-activated protein glucocorticoid receptor, and hepatic nuclear factor 4 alpha. Mol kinase (AMPK) independent manner. J Toxicol Sci 35:571–576 Pharmacol 68:747–757 Kawamoto T, Sueyoshi T, Zelko I, Moore R, Washburn K, Negishi M Forman BM, Tzameli I, Choi HS, Chen J, Simha D, Seol W, Evans (1999) Phenobarbital-responsive nuclear translocation of the recep- RM, Moore DD (1998) Androstane metabolites bind to and tor CAR in induction of the CYP2B gene. Mol Cell Biol 19:6318–6322 deactivate the nuclear receptor CAR-beta. Nature 395:612–615 Kietzmann T, Hirsch-Ernst KI, Kahl GF, Jungermann K (1999) Gao J, He J, Zhai Y, Wada T, Xie W (2009) The constitutive Mimicry in primary rat hepatocyte cultures of the in vivo perive- androstane receptor is an anti-obesity nuclear receptor that nous induction by phenobarbital of cytochrome P-450 2B1 improves insulin sensitivity. J Biol Chem 284:25984–25992 mRNA: role of epidermal growth factor and perivenous oxygen Gerbal-Chaloin S, Daujat M, Pascussi JM, Pichard-Garcia L, Vilarem tension. Mol Pharmacol 56:46–53 MJ, Maurel P (2002) Transcriptional regulation of CYP2C9 gene.
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T xas Node Newsletter Trivedi's Thoughts Dear Texas Node, This is the time where we all have undoubtedly reflected upon our accomplishments of the past year and are now in the midst of working Volume 2, Issue 1 toward our goals for this year. I'd like to take this opportunity to provide a ‘State of the Node' update. Last year was eventful and productive on many fronts. Study

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MINISTERIO DE LA PRESIDENCIA DIRECCION ADMINISTRATIVA INFORME DE INGRESOS Y GASTOS FONDO PROGRAMA DEL DESPACHO SUPERIOR Del 1 de Julio de 2007 al 30 de Septiembre de 2007 Transferencias recibidas del Tesoro Nacional y otros Reembolso H.D. Jorge Alvarado 7894612 Depósito MEF No.7122110 Nota de crédito por reembolso de gastos médicos San Vicente de Paul de Colombia del el joven Gilberto Araúz por