of Work: Metabolism by cytochromes P450 and specific transferases is a defense system against environmental toxicants and carcinogens. To encounter virtually unlimited numbers of structurally diverse xenochemicals, P450 and transferase genes are capable of being induced in response to chemical exposures and increase their metabolic capability. Finding the induction mechanism is critical for our ability to predict human susceptability to the exposures. Phenobarbital (PB) is the prototype of a large number of chemicals that induce the sets of P450 and transferase genes. We have now defined the conserved 51-bp DNA found in these genes (in mouse, rat, and human) as the PB-responsive enhancer module or PBREM. We have also identified the nuclear orphan receptor CAR that activates PBREM in response to PB induction. PB induction was found to be defected in rats in which CAR function is impaired, which include genetically engineered CAR-null mice. In addition to numerous PB-type inducers, endgenous steroid hormones regulate the receptor CAR; estrogens are activators while androgens and progesterone are repressors. CAR is a cytosolic receptor in non-induced livers and translocates to nucleus following PB treatment. Cytosolic CAR complex recruites protein phosphase 2A for the nuclear translocation. Establishing a system in which endodogenous CAR can be expressed in liver cells, we found that the C-terminal LXXLXXL sequence regulates the PB-inducible nuclear translocation of CAR.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES080040-17
Application #
6681992
Study Section
(LRDT)
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2002
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Konno, Yoshihiro; Kodama, Susumu; Moore, Rick et al. (2009) Nuclear xenobiotic receptor pregnane X receptor locks corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) onto the CYP24A1 promoter to attenuate vitamin D3 activation. Mol Pharmacol 75:265-71
Adair, Jennifer E; Stober, Vandy; Sobhany, Mack et al. (2009) Inter-alpha-trypsin inhibitor promotes bronchial epithelial repair after injury through vitronectin binding. J Biol Chem 284:16922-30
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Timsit, Yoav E; Negishi, Masahiko (2007) CAR and PXR: the xenobiotic-sensing receptors. Steroids 72:231-46
Nakamura, Kouichi; Moore, Rick; Negishi, Masahiko et al. (2007) Nuclear pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse liver. J Biol Chem 282:9768-76
Yamazaki, Yuichi; Kakizaki, Satoru; Horiguchi, Norio et al. (2007) The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis. Gut 56:565-74
Phillips, Jennifer M; Yamamoto, Yukio; Negishi, Masahiko et al. (2007) Orphan nuclear receptor constitutive active/androstane receptor-mediated alterations in DNA methylation during phenobarbital promotion of liver tumorigenesis. Toxicol Sci 96:72-82
Sobhany, Mack; Negishi, Masahiko (2006) Characterization of specific donor binding to alpha1,4-N-acetylhexosaminyltransferase EXTL2 using isothermal titration calorimetry. Methods Enzymol 416:3-12
Inoue, Kaoru; Borchers, Christoph H; Negishi, Masahiko (2006) Cohesin protein SMC1 represses the nuclear receptor CAR-mediated synergistic activation of a human P450 gene by xenobiotics. Biochem J 398:125-33

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