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First published on October 18, 2004; DOI: 10.1124/mol.104.002410

0026-895X/05/6701-88-96$20.00
Mol Pharmacol 67:88-96, 2005

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Multiple Mechanisms Are Involved in Ah Receptor-Mediated Cell Cycle Arrest

Gengming Huang, and Cornelis J. Elferink

Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas

The liver is the only solid organ that can respond to major tissue loss or damage by regeneration to restore liver biomass. The aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can disrupt the regenerative process, as evidenced by suppression of DNA synthesis in rat primary hepatocytes in culture and in vivo liver regeneration after partial hepatectomy. Independent observations demonstrated that AhR-mediated G1 phase cell cycle arrest depends on an interaction with the retinoblastoma tumor suppressor protein (pRb), but differences exist regarding proposed mechanisms of action. Two distinct models have been proposed, one supporting the AhR-pRb interaction functioning in corepression of E2F activity and the other favoring an AhR-pRb interaction participating in transcriptional coactivation of genes encoding G1 phase regulatory proteins. In the present study, experiments in rat hepatoma cells using dominant-negative DNA-binding-defective AhR and Ah receptor nuclear translocator (Arnt) mutants provided evidence that TCDD-induced AhR-mediated G1 arrest is only partially regulated by direct AhR transcriptional activity, suggesting that both coactivation and corepression are involved. Studies using a small interfering RNA to down-regulate Arnt protein expression revealed that TCDD-induced G1 arrest is absolutely dependent on the Arnt protein.

Received for publication May 6, 2004.

Accepted for publication October 14, 2004.

Address correspondence to: Dr. Cornelis J. Elferink, Assistant Professor, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX. E-mail: coelferi{at}utmb.edu




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