Cytochrome P4501A1 promotes G1 phase cell cycle progression by controlling aryl hydrocarbon receptor activity
Cytochrome P4501A1 promotes G1 phase cell cycle progression by controlling aryl hydrocarbon receptor activity
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DOI：
10.1124/mol.65.2.461
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发表时间：
2004-02-01
影响因子：
3.6
通讯作者：
Elferink, CJ
中科院分区：
文献类型：
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作者：
Levine-Fridman, A;Chen, L;Elferink, CJ
芳香烃受体（AhR）转录因子越来越多地被认为在细胞周期控制中起作用。最近的一些报道表明，在不存在外源性激动剂或存在原型配体2，3，7，8-四氯二苯并-p-二恶英的情况下，AhR活性可以影响培养细胞中的G（1）期进展。血清饥饿（G（0））5L大鼠肝癌细胞的血清释放触发瞬时AhR激活和P4501 A1蛋白表达伴随G（0）/G（1）-到-S相变。相反，TCDD处理后持续的AhR激活除了增加P4501 A1的表达外，还增加了p27（Kip 1）的表达，导致G（1）期细胞周期停滞。用基于炔代谢的P4501 A1抑制剂1-（1-丙炔基）芘处理血清释放的5L细胞导致延长的AhR激活、增强的p27（Kip 1）表达和血清释放后的G（1）期停滞。这些数据与P4501 A1的细胞周期作用一致，因为它们表明P4501 A1通过代谢清除受体激动剂负调节AhR作用的持续时间，从而防止AhR介导的G（1）期阻滞。
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 G(1) phase progression in cultured cells. Serum release of serum-starved (G(0)) 5L rat hepatoma cells triggers transient AhR activation and P4501A1 protein expression concomitant with the G(0)/G(1)-to-S phase transition. In contrast, sustained AhR activation in response to TCDD treatment increases p27(Kip1) expression in addition to P4501A1, resulting in G(1) 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 G(1) 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 G(1) phase arrest.