Role of cytochrome P4501A1 in cell cycle progression

描述（由申请人提供）：芳烃受体（AhR）是一种配体激活的转录因子，被广泛认为可介导环境污染物（例如2,3,7,8-四氯二苯并-对二恶英（TCDD））的毒性。接触 TCDD 会抑制多种细胞类型的增殖并引发 G1 细胞周期停滞，表明 AhR 激活会损害细胞周期进程。同样，AhR 缺陷细胞表现出改变的增殖反应，与 AhR 在细胞周期进展中的作用一致。因此，调节 AhR 活性的过程将影响细胞周期的运动。最近的研究结果表明，细胞色素 P4501A1 可以通过代谢消耗生理受体配体来终止 AhR 活性。由于 AhR 控制编码 P4501A1 蛋白的 CYP1A1 基因的表达，因此 CYP1A1 的诱导建立了一个负反馈环，抑制持续的 AhR 活性。这赋予 P4501A1 在 G1 期细胞周期进展中的积极作用。本研究的目的是测试 P4501A1 在体内肝再生过程中和体外原代肝细胞中肝细胞增殖中的生理作用。

DESCRIPTION (provided by applicant): 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.