A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein - Linking dioxin signaling to the cell cycle
A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein - Linking dioxin signaling to the cell cycle
复制标题
DOI：
10.1074/jbc.273.35.22708
复制
发表时间：
1998-08-28
影响因子：
4.8
通讯作者：
Elferink, CJ
中科院分区：
文献类型：
--
作者：
Ge, NL;Elferink, CJ
芳香烃受体（aryl hydrocarbon receptor，AhR）是真核细胞中的一种配体激活的转录因子，在环境污染物2，3，7，8-四氯二苯并-对-二恶英（tetrachlorodibenzo-p-dioxin，TCDD）的作用下改变基因表达。视网膜母细胞瘤肿瘤抑制蛋白（pRb）控制细胞周期通过G（1）进程，除了促进分化外，我们还研究了人类AhR或其二聚化伴侣AhR核转运蛋白是否与pRb相互作用，作为TCDC诱导的基础细胞周期停滞。在体内和体外试验揭示了直接之间的相互作用pRb和AhR，但不是AhR核转位蛋白。AhR和pRb之间的结合通过AhR中的两个不同区域发生。高亲和力位点位于AhR的N-末端364个氨基酸内，而较低亲和力结合区与受体的富含谷氨酰胺的反式激活结构域共定位。AhR配体结合是不需要的pRb相互作用本身，虽然在5L细胞中的免疫沉淀实验表明，pRb协会优先与配体AhR，配体诱导的核转位的要求一致。这些观察结果提供了一个机制的见解AhR介导的细胞周期阻滞和TCDD诱导的毒性的新视角。
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor in eukaryotic cells that alters gene expression in response to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), In 5L hepatoma cells, TCDD induces a G(1), cell cycle arrest through a mechanism that involves the AhR. The retinoblastoma tumor suppressor protein (pRb) controls cell cycle progression through G(1), in addition to promoting differentiation, We examined whether the human AhR or its dimerization partner, the AhR nuclear translocator, interacts with pRb as a basis of the TCDD-induced cell cycle arrest. In vivo and in vitro assays reveal a direct interaction between pRb and the AhR but not the AhR nuclear translocator protein. Binding between the AhR and pRb occurs through two distinct regions in the AhR. A high affinity site lies within the N-terminal 364 amino acids of the AhR, whereas a lower affinity binding region colocalizes with the glutamine-rich transactivation domain of the receptor. AhR ligand binding is not required for the pRb interaction per se, although immunoprecipitation experiments in 5L cells reveal that pRb associates preferentially with the liganded AhR, consistent with a requirement for ligand-induced nuclear translocation. These observations provide a mechanistic insight into AhR-mediated cell cycle arrest and a new perspective on TCDD-induced toxicity.