Authors: Kristen A. Mitchell
Affiliation:
Title: In vivo regulation of hepatocyte proliferation by the aryl hydrocarbon receptor
Abstract: The aryl hydrocarbon receptor (AhR) is a soluble, ligand-activated transcription factor in the basic helix-loop-helix family of proteins that function during environmental stress. Exogenous AhR ligands include the potent and persistent pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Upon ligand binding, the AhR translocates to the nucleus and dimerizes with the Ah receptor nuclear translocator (ARNT) to form a transcriptionally active complex. AhR-mediated alterations in gene expression likely contribute to most of the toxic effects associated with TCDD, which include immunosuppression, teratogenesis, and carcinogenesis. However, little is known about endogenous AhR function, as a bona fide endogenous ligand has not been identified, and the physiological role of this receptor is unclear. Emerging evidence demonstrates that endogenous AhR signaling is required for normal hepatocyte proliferation to occur. When such signaling is disrupted by removing the AhR, or else by activating it with a persistent, poorly metabolized agonist such as TCDD, hepatocyte-derived cell lines exhibit a G1 cell cycle arrest. We have used an in vivo model system of murine liver regeneration induced by 70% partial hepatectomy (PH) to demonstrate a similar G1 arrest in the regenerating liver of mice treated with TCDD. This arrest coincides with reduced activity of cyclin-dependent kinases (CDKs) and changes in the association of CDKs with regulatory proteins. To reconcile these findings with the established tumor-promoting effects of TCDD, it has been proposed that TCDD-mediated inhibition of hepatocyte proliferation confers a growth advantage on transformed hepatocytes, facilitating the development of hepatocarcinogenesis. Along these lines, we examined the consequences of TCDD treatment on hepatocyte proliferation in mice treated with the potent hepatomitogen 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP). In contrast to the suppressive effects of TCDD observed during liver regeneration, pretreatment of mice with TCDD prior to TCPOBOP administration resulted in increased hepatocyte proliferation, with a concomitant increase in G1 kinase activity and S-phase progression. The disparate effects of TCDD observed during liver regeneration and mitogen-induced liver hyperplasia suggest that the consequences of exogenous AhR activation depend on the individual mitogenic stimulus. From a mechanistic standpoint, altered G1 kinase activity in each model system suggests a physiologically relevant role for the AhR in regulating the assembly and/or function of G1 protein complexes that facilitate S-phase progression.