| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Molecular and Cellular Biology (W.H., J.Z., M.W., J.L., D.D.M.), Baylor College of Medicine, and Department of Molecular Genetics (J.M.P., G.L.), University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
Address all correspondence and requests for reprints to: David D. Moore, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030. E-mail: moore{at}bcm.tmc.edu.
The constitutive androstane receptor (CAR, NR1I3) is a central regulator of xenobiotic metabolism. CAR activation induces hepatic expression of detoxification enzymes and transporters and increases liver size. Here we show that CAR-mediated hepatomegaly is a transient, adaptive response to acute xenobiotic stress. In contrast, chronic CAR activation results in hepatocarcinogenesis. In both acute and chronic xenobiotic responses, hepatocyte DNA replication is increased and apoptosis is decreased. These effects are absent in CAR null mice, which are completely resistant to tumorigenic effects of chronic xenobiotic stress. In the acute response, direct up-regulation of Mdm2 expression by CAR contributes to both increased DNA replication and inhibition of p53-mediated apoptosis. These results demonstrate an essential role for CAR in regulating both liver homeostasis and tumorigenesis in response to xenobiotic stresses, and they also identify a specific molecular mechanism linking chronic environmental stress and tumor formation.
NURSA Molecule Pages Link:
This article has been cited by other articles:
 |
|
 |
|
  Y. Yamamoto and M. Negishi The Antiapoptotic Factor Growth Arrest and DNA-Damage-Inducible 45 {beta} Regulates the Nuclear Receptor Constitutive Active/Androstane Receptor-Mediated Transcription Drug Metab. Dispos., July 1, 2008; 36(7): 1189 - 1193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Rosen, J. S. Lee, H. Ren, B. Vallanat, J. Liu, M. P. Waalkes, B. D. Abbott, C. Lau, and J. C. Corton Toxicogenomic Dissection of the Perfluorooctanoic Acid Transcript Profile in Mouse Liver: Evidence for the Involvement of Nuclear Receptors PPAR{alpha} and CAR Toxicol. Sci., May 1, 2008; 103(1): 46 - 56. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhou, M. Liu, Y. Zhai, and W. Xie The Antiapoptotic Role of Pregnane X Receptor in Human Colon Cancer Cells Mol. Endocrinol., April 1, 2008; 22(4): 868 - 880. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Sueyoshi, R. Moore, J. Sugatani, Y. Matsumura, and M. Negishi PPP1R16A, The Membrane Subunit of Protein Phosphatase 1{beta}, Signals Nuclear Translocation of the Nuclear Receptor Constitutive Active/Androstane Receptor Mol. Pharmacol., April 1, 2008; 73(4): 1113 - 1121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kiyosawa, J. C. Kwekel, L. D. Burgoon, K. J. Williams, C. Tashiro, B. Chittim, and T. R. Zacharewski o,p'-DDT Elicits PXR/CAR-, Not ER-, Mediated Responses in the Immature Ovariectomized Rat Liver Toxicol. Sci., February 1, 2008; 101(2): 350 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Guo, J. Sarkar, K. Suino-Powell, Y. Xu, K. Matsumoto, Y. Jia, S. Yu, S. Khare, K. Haldar, M. S. Rao, et al. Induction of Nuclear Translocation of Constitutive Androstane Receptor by Peroxisome Proliferator-activated Receptor {alpha} Synthetic Ligands in Mouse Liver J. Biol. Chem., December 14, 2007; 282(50): 36766 - 36776. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Peffer, J. G. Moggs, T. Pastoor, R. A. Currie, J. Wright, G. Milburn, F. Waechter, and I. Rusyn Mouse Liver Effects of Cyproconazole, a Triazole Fungicide: Role of the Constitutive Androstane Receptor Toxicol. Sci., September 1, 2007; 99(1): 315 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. G. Woods, J. P. Vanden Heuvel, and I. Rusyn Genomic Profiling in Nuclear Receptor-Mediated Toxicity Toxicol Pathol, June 1, 2007; 35(4): 474 - 494. [Abstract] [PDF]
|
|
|
|
|
|
J. M. Phillips, Y. Yamamoto, M. Negishi, R. R. Maronpot, and J. I. Goodman Orphan Nuclear Receptor Constitutive Active/Androstane Receptor-Mediated Alterations in DNA Methylation during Phenobarbital Promotion of Liver Tumorigenesis Toxicol. Sci., March 1, 2007; 96(1): 72 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Tien, K. Matsui, R. Moore, and M. Negishi The Nuclear Receptor Constitutively Active/Androstane Receptor Regulates Type 1 Deiodinase and Thyroid Hormone Activity in the Regenerating Mouse Liver J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 307 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. D. Moore, S. Kato, W. Xie, D. J. Mangelsdorf, D. R. Schmidt, R. Xiao, and S. A. Kliewer International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor {alpha}, Farnesoid X Receptor beta, Liver X Receptor {alpha}, Liver X Receptor beta, and Vitamin D Receptor Pharmacol. Rev., December 1, 2006; 58(4): 742 - 759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Nelson, V. Bhaskaran, W. R. Foster, and L. D. Lehman-McKeeman p53-Independent Induction of Rat Hepatic Mdm2 following Administration of Phenobarbital and Pregnenolone 16{alpha}-Carbonitrile Toxicol. Sci., December 1, 2006; 94(2): 272 - 280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Sakai, H. Iwata, E.-Y. Kim, O. Tsydenova, N. Miyazaki, E. A. Petrov, V. B. Batoev, and S. Tanabe Constitutive Androstane Receptor (CAR) as a Potential Sensing Biomarker of Persistent Organic Pollutants (POPs) in Aquatic Mammal: Molecular Characterization, Expression Level, and Ligand Profiling in Baikal Seal (Pusa sibirica) Toxicol. Sci., November 1, 2006; 94(1): 57 - 70. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
