Article

Nuclear receptor CAR represses TNFα-induced cell death by interacting with the anti-apoptotic GADD45B

Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America.
PLoS ONE (Impact Factor: 3.23). 04/2010; 5(4):e10121. DOI: 10.1371/journal.pone.0010121
Source: PubMed

ABSTRACT

Phenobarbital (PB) is the most well-known among numerous non-genotoxic carcinogens that cause the development of hepatocellular carcinoma (HCC). PB activates nuclear xenobiotic receptor Constitutive Active/Androstane Receptor (CAR; NR1I3) and this activation is shown to determine PB promotion of HCC in mice. The molecular mechanism of CAR-mediated tumor promotion, however, remains elusive at the present time. Here we have identified Growth Arrest and DNA Damage-inducible 45β (GADD45B) as a novel CAR target, through which CAR represses cell death.

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Available from: Richard A Flavell
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    • "To date, many groups have reported possible mechanisms for the CAR-mediated hepatocyte proliferation in mice. For example, CAR induced the transcription of the genes encoding modulators of p53 tumor suppressor protein, such as Gadd45 and Mdm2 [9], [10], [11]. Another report demonstrated that CAR-induced hepatocyte hyperplasia was mediated by the expression of the oncogene c-Myc and its target Foxm1 [12]. "
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    ABSTRACT: Xenobiotic-responsive nuclear receptors pregnane X receptor (PXR), constitutive active/androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα) play pivotal roles in the metabolic functions of the liver such as xenobiotics detoxification and energy metabolism. While CAR or PPARα activation induces hepatocyte proliferation and hepatocarcinogenesis in rodent models, it remains unclear whether PXR activation also shows such effects. In the present study, we have investigated the role of PXR in the xenobiotic-induced hepatocyte proliferation with or without CAR activation by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and phenobarbital, or PPARα activation by Wy-14643 in mice. Treatment with TCPOBOP or phenobarbital increased the percentage of Ki-67-positive nuclei as well as mRNA levels of cell proliferation-related genes in livers as expected. On the other hand, treatment with the PXR activator pregnenolone 16α-carbonitrile (PCN) alone showed no such effects. Surprisingly, PCN co-treatment significantly augmented the hepatocyte proliferation induced by CAR activation with TCPOBOP or phenobarbital in wild-type mice but not in PXR-deficient mice. Intriguingly, PXR activation also augmented the hepatocyte proliferation induced by Wy-14643 treatment. Moreover, PCN treatment increased the RNA content of hepatocytes, suggesting the induction of G0/G1 transition, and reduced mRNA levels of Cdkn1b and Rbl2, encoding suppressors of cell cycle initiation. Our present findings indicate that xenobiotic-induced hepatocyte proliferation mediated by CAR or PPARα is enhanced by PXR co-activation despite that PXR activation alone does not cause the cell proliferation in mouse livers. Thus PXR may play a novel and unique role in the hepatocyte/liver hyperplasia upon exposure to xenobiotics.
    Full-text · Article · Apr 2013 · PLoS ONE
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    • "These genes may play critical roles in developing hepatic hypertrophy and/or hyperplasia as well as the subsequent HCC development. Various genes were previously suggested as candidates responsible for phenobarbital-promoted HCC development, such as Mmd2, Foxm1b, Gadd45β, and c-Myc (Blanco-Bose et al., 2008; Huang et al., 2005; Kalinichenko et al., 2004; Yamamoto et al., 2010). However, until now no such gene with this specificity and dependency has been known. "
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    ABSTRACT: KCNK1, a member of the family of two-pore K+ ion channels, is specifically induced in the livers of male mice after phenobarbital treatment. Here we have determined the molecular mechanism of this male-specific activation of the Kcnk1 gene and characterized KCNK1 as a phenobarbital-inducible anti-hyperplasia factor. Upon activation by phenobarbital, nuclear receptor CAR binds the 97-bp response element (-2,441/-2,345) within the Kcnk1 promoter. This binding is observed in the livers of male, but not female, mice, and requires the pituitary gland, since hypophysectomy abrogates it. Hyperplasia further progressed in the livers of Kcnk1-/- male mice compared with those of Kcnk1+/+ males after phenobarbital treatment. Thus, KCNK1 suppresses phenobarbital-induced hyperplasia. These results indicate that phenobarbital treatment induces KCNK1 to elicit a male specific and growth-suppressing signal. Thus, KCNK1 and Kcnk1-/- mice provide an experimental tool for further investigation into the molecular mechanism of CAR-mediated promotion of the development of hepatocellular carcinoma in mice.
    Full-text · Article · Jan 2013 · Toxicological Sciences
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    • "The reasons for these apparent differences are not clear but may lie in the nature of the mouse models used to generate the results. Mechanistically, GADD45B (Yamamoto et al., 2010), an antiapoptotic factor, as well as Mdm2 (Huang et al., 2005), a negative regulator of the p53 tumor suppressor, have been implicated as pathways activated by CAR and contributory to the enhanced tumorigenic response in CAR wild-type animals. "
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    ABSTRACT: To commemorate the 50th anniversary of the Society of Toxicology, this special edition article reviews the history and current scope of xenobiotic metabolism and transport, with special emphasis on the discoveries and impact of selected "xenobiotic receptors." This overall research realm has witnessed dynamic development in the past 50 years, and several of the key milestone events that mark the impressive progress in these areas of toxicological sciences are highlighted. From the initial observations regarding aspects of drug metabolism dating from the mid- to late 1800's, the area of biotransformation research witnessed seminal discoveries in the mid-1900's and onward that are remarkable in retrospect, including the discovery and characterization of the phase I monooxygenases, the cytochrome P450s. Further research uncovered many aspects of the biochemistry of xenobiotic metabolism, expanding to phase II conjugation and phase III xenobiotic transport. This led to hallmark developments involving integration of genomic technologies to elucidate the basis for interindividual differences in response to xenobiotic exposures and discovery of nuclear and soluble receptor families that selectively "sense" the chemical milieu of the mammalian cell and orchestrate compensatory changes in gene expression programming to accommodate complex xenobiotic exposures. This review will briefly summarize these developments and investigate the expanding roles of xenobiotic receptor biology in the underlying basis of toxicological response to chemical agents.
    Full-text · Article · Nov 2010 · Toxicological Sciences
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