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Cytochrome P4501A1 Promotes G₁ Phase Cell Cycle Progression by Controlling Aryl Hydrocarbon Receptor Activity

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

The aryl hydrocarbon receptor (AhR) transcription factor is increasingly recognized as functioning in cell cycle control. Several recent reports have shown that AhR activity in the absence of exogenous agonists or presence of the prototypical ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin can affect G₁ phase progression in cultured cells. Serum release of serum-starved (G₀) 5L rat hepatoma cells triggers transient AhR activation and P4501A1 protein expression concomitant with the G₀/G₁-to-S phase transition. In contrast, sustained AhR activation in response to TCDD treatment increases p27^Kip1 expression in addition to P4501A1, resulting in G₁ phase cell cycle arrest. Treating serum-released 5L cells with the alkyne metabolism-based P4501A1 inhibitor 1-(1-propynyl)pyrene results in prolonged AhR activation, enhanced p27^Kip1 expression, and G₁ phase arrest after serum release. The data are consistent with a cell cycle role for P4501A1 because they show that P4501A1 negatively regulates the duration of AhR action through the metabolic removal of the receptor agonist, thereby preventing AhR-mediated G₁ phase arrest.

Address correspondence to: Dr. Cornelis J. Elferink, Assistant Professor, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1031. E-mail: coelferi{at}utmb.edu

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