Institute of Toxicology, University of Tübingen, Tübingen D-72074, Germany.
Environ Toxicol Pharmacol. 1998 Dec 1;6(4):239-47. doi: 10.1016/s1382-6689(98)00040-4.
Inhibition of apoptosis of preneoplastic cells is thought to represent a major mechanism of action of tumor promoters. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent promoter of liver carcinogenesis in rodents, suppressed apoptosis in rat hepatocytes pretreated in vitro with an apoptogenic dose of UV light. This effect, which was also observable in DNA fragmentation analysis, coincided with a pronounced inhibition of the p53 increase usually seen after UV irradiation of rat hepatocytes. Interestingly, TCDD also led to a very minor but consistent enhancement of DNA fragmentation and to a slight increase in p53. Furthermore, TCDD resulted in a dose-dependent increase in p53 phosphorylation in intact cells. The concentration-response curves of the effects of TCDD on p53 phosphorylation and aromatic hydrocarbon receptor (AhR)-dependent induction of cytochrome P450 1A1 activity were almost superimposable, suggesting that TCDD induces p53 phosphorylation via an AhR-linked kinase activity. In an extract prepared from rat liver homogenate, 1 nM TCDD also stimulated p53 phosphorylation. Since the tyrosine kinase c-src was previously shown by others to be activated upon binding of TCDD to the AhR, extracts were pretreated with anti-src-antibodies. This treatment almost completely abrogated the effect of TCDD on p53 phosphorylation suggesting a key role for AhR-associated c-src. This mode of action may result in the observed suppression of the p53 response to apoptogenic UV irradiation, and may contribute to the inhibition of apoptosis.
抑制癌前细胞的凋亡被认为是肿瘤促进剂的主要作用机制。2,3,7,8-四氯二苯并-p-二恶英（TCDD）是最有效的鼠类肝脏致癌促进剂，它可抑制经体外预用致凋亡剂量紫外线照射的大鼠肝细胞中的凋亡。这种效应在 DNA 片段化分析中也可观察到，与大鼠肝细胞经紫外线照射后通常出现的 p53 增加明显抑制相一致。有趣的是，TCDD 还导致 DNA 片段化的轻微但一致的增强和 p53 的轻微增加。此外，TCDD 导致完整细胞中 p53 磷酸化的剂量依赖性增加。TCDD 对 p53 磷酸化和芳香烃受体（AhR）依赖性细胞色素 P450 1A1 活性诱导的影响的浓度-反应曲线几乎完全重叠，表明 TCDD 通过 AhR 连接的激酶活性诱导 p53 磷酸化。在从大鼠肝匀浆中制备的提取物中，1 nM TCDD 也刺激了 p53 磷酸化。由于先前已经表明酪氨酸激酶 c-src 在 TCDD 与 AhR 结合时被激活，因此提取物用抗-src 抗体进行预处理。该处理几乎完全消除了 TCDD 对 p53 磷酸化的影响，提示 AhR 相关的 c-src 起着关键作用。这种作用模式可能导致观察到的对致凋亡紫外线照射的 p53 反应的抑制，并可能有助于抑制凋亡。
