Role of cytochrome P4501A1 in cell cycle progression

描述(申请人提供)：芳烃受体(AhR)是一种配体激活的转录因子，被广泛认为是介导环境污染物如2，3，7，8-四氯二苯并-对二恶英(TCDD)的毒性。暴露于TCDD可抑制多种细胞类型的增殖并引起G1期细胞周期停滞，这表明AhR的激活损害了细胞周期进程。同样，AhR缺陷细胞表现出改变的增殖反应，这与AhR在细胞周期进程中的作用一致。因此，调节AhR活性的过程将影响细胞周期中的运动。最近的研究表明，细胞色素P4501A1可以通过代谢耗尽生理受体配体来终止AhR的活性。由于AhR控制编码P4501A1蛋白的CYP1A1基因的表达，因此诱导CYP1A1建立了一个负反馈环，抑制了AhR的持续活性。这使P4501A1在G1期细胞周期进程中发挥积极作用。这项研究的目的是测试P4501A1在体内肝再生和体外原代肝细胞中对肝细胞增殖的生理作用。

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.