p27Kip1 induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells
p27Kip1 induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells
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DOI：
10.1101/gad.13.13.1742
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发表时间：
1999-07-01
影响因子：
10.5
通讯作者：
Göttlicher, M
中科院分区：
文献类型：
--
作者：
Kolluri, SK;Weiss, C;Göttlicher, M
Ah受体（AhR）是一种bHLH/PAS转录因子，介导免疫系统、皮肤、睾丸和肝脏中的二恶英毒性。毒性现象与细胞增殖或分化的改变有关，但对AhR在细胞周期调控中的信号通路知之甚少。在这里，我们表明，AhR诱导p27（Kip 1）细胞周期蛋白/cdk抑制剂通过改变Kip 1转录在一个直接的模式，而不需要进行蛋白质合成或细胞增殖。这是Kip 1作为影响细胞增殖的毒性剂的直接转录靶点的第一个例子。Kip 1导致二恶英诱导的5L肝癌细胞增殖抑制，因为Kip 1反义表达细胞对二恶英具有抗性。Kip 1也被二恶英诱导，在胎儿胸腺的培养物中伴随着增殖的抑制和胸腺细胞恢复的严重减少。Kip 1表达可能介导这些效应，因为Kip 1缺陷小鼠的胸腺（Kip 1（Delta 51））虽然不是完全抵抗，但在很大程度上是抵抗的。
The Ah receptor (AhR), a bHLH/PAS transcription factor, mediates dioxin toxicity in the immune system, skin, testis and liver. Toxic phenomena are associated with altered cell proliferation or differentiation, but signaling pathways of AhR in cell cycle regulation are poorly understood. Here we show that AhR induces the p27(Kip1) cyclin/cdk inhibitor by altering Kip1 transcription in a direct mode without the need for ongoing protein synthesis or cell proliferation. This is the first example of Kip1 being a direct transcriptional target of a toxic agent that affects cell proliferation. Kip1 causes dioxin-induced suppression of 5L hepatoma cell proliferation because Kip1 antisense-expressing cells are resistant to dioxins. Kip1 is also induced by dioxins in cultures of fetal thymus glands concomitant with inhibition of proliferation and severe reduction of thymocyte recovery. Kip1 expression is likely to mediate these effects as thymic glands of Kip1-deficient mice (Kip1(Delta 51)) are largely, though not completely, resistant.