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

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Received for publication May 10, 2004.
Revised October 14, 2004.
Accepted for publication October 14, 2004.

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

Gengming Huang 1 Cornelis J. Elferink 1*

1 University of Texas Medical Branch

* Address correspondence to: E-mail: coelferi{at}utmb.edu

Abstract

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 following 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 put forward, one supporting the AhR-pRb interaction functioning in corepression of E2F activity, 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 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.


Key words: Transcriptional coactivators, Ah receptor, RNA/siRNA, Tumor suppressors


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