The CAR (constitutive androstane receptor; NR1I3) is a critical xenobiotic sensor that regulates xenobiotic metabolism, drug clearance, energy and lipid homoeostasis, cell proliferation and development. Although constitutively active, in hepatocytes CAR is normally held quiescent through a tethering mechanism in the cytosol, anchored to a protein complex that includes several components, including heat-shock protein 90. Release and subsequent nuclear translocation of CAR is triggered through either direct binding to ligand activators such as CITCO {6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime} or through indirect chemical activation, such as with PB (phenobarbital). In the present study, we demonstrate that proteasomal inhibition markedly disrupts CAR function, repressing CAR nuclear trafficking, disrupting CAR's interaction with nuclear co-activators and inhibiting induction of CAR target gene responses in human primary hepatocytes following treatment with either PB or CITCO. Paradoxically, these effects occur following accumulation of ubiquitinated hCAR (human CAR). Furthermore, a non-proteolytic function was indicated by its interaction with a SUG1 (suppressor for Gal1), a subunit of the 26S proteasome. Taken together, these data demonstrate that the proteasome complex functions at multiple levels to regulate the functional biology of hCAR activity.
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Research Article|
January 20 2014
Proteasomal interaction as a critical activity modulator of the human constitutive androstane receptor
Tao Chen;
Tao Chen
*Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 101 Life Sciences Building, Pennsylvania State University, University Park, PA 16802, U.S.A.
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Elizabeth M. Laurenzana;
Elizabeth M. Laurenzana
*Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 101 Life Sciences Building, Pennsylvania State University, University Park, PA 16802, U.S.A.
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Denise M. Coslo;
Denise M. Coslo
*Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 101 Life Sciences Building, Pennsylvania State University, University Park, PA 16802, U.S.A.
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Fengming Chen;
Fengming Chen
*Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 101 Life Sciences Building, Pennsylvania State University, University Park, PA 16802, U.S.A.
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Curtis J. Omiecinski
Curtis J. Omiecinski
1
*Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 101 Life Sciences Building, Pennsylvania State University, University Park, PA 16802, U.S.A.
1To whom correspondence should be addressed (email cjo10@psu.edu).
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Publisher: Portland Press Ltd
Received:
May 20 2013
Revision Received:
October 29 2013
Accepted:
November 14 2013
Accepted Manuscript online:
November 14 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 458 (1): 95–107.
Article history
Received:
May 20 2013
Revision Received:
October 29 2013
Accepted:
November 14 2013
Accepted Manuscript online:
November 14 2013
Citation
Tao Chen, Elizabeth M. Laurenzana, Denise M. Coslo, Fengming Chen, Curtis J. Omiecinski; Proteasomal interaction as a critical activity modulator of the human constitutive androstane receptor. Biochem J 15 February 2014; 458 (1): 95–107. doi: https://doi.org/10.1042/BJ20130685
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