The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor widely recognized for mediating the toxicity of environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Exposure to TCDD suppresses proliferation and elicits a G1 cell cycle arrest in numerous cell types, suggesting that AhR activation impairs cell cycle progression. Likewise, AhR-defective cells exhibit altered proliferative responses, consistent with a role for the AhR in cell cycle progression. Hence, processes that regulate AhR activity will influence movement through the cell cycle. Recent findings revealed that cytochrome P4501A1 can terminate AhR activity by metabolically depleting the physiological receptor ligand. Since the AhR controls expression of the CYP1A1 gene encoding the P4501A1 protein, induction of CYP1A1 establishes a negative feedback loop suppressing continued AhR activity. This confers upon P4501A1 a positive role in G1 phase cell cycle progression. The goal of the proposed research is to test the physiological role of P4501A1 in hepatocyte proliferation during liver regeneration in vivo and in primary hepatocytes in vitro.
| Mitchell, Kristen A; Wilson, Shelly R; Elferink, Cornelis J (2010) The activated aryl hydrocarbon receptor synergizes mitogen-induced murine liver hyperplasia. Toxicology 276:103-9 |
| Mitchell, Kristen A; Elferink, Cornelis J (2009) Timing is everything: consequences of transient and sustained AhR activity. Biochem Pharmacol 77:947-56 |
| Mitchell, Kristen A; Lockhart, Courtney A; Huang, Gengming et al. (2006) Sustained aryl hydrocarbon receptor activity attenuates liver regeneration. Mol Pharmacol 70:163-70 |
| Park, Kyung-Tae; Mitchell, Kristen A; Huang, Gengming et al. (2005) The aryl hydrocarbon receptor predisposes hepatocytes to Fas-mediated apoptosis. Mol Pharmacol 67:612-22 |
