Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors
Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors
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DOI：
10.1093/carcin/20.9.1819
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发表时间：
1999-09-01
期刊：
影响因子：
4.7
通讯作者：
Costa, M
中科院分区：
文献类型：
--
作者：
Salnikow, K;An, WG;Costa, M
镍（Ni）化合物是一种强致癌物，可诱导啮齿动物和人类细胞的恶性转化。为了阐明镍诱导转化的分子机制，我们研究了镍转化细胞中低氧诱导因子（HIF-1）和p53肿瘤抑制蛋白的转录活性。我们证明，在镍转化的啮齿动物细胞中，HIF-1应答启动子的活性增加，导致HIF-1和p53刺激的转录比例增加。为了进一步阐明HIF-1和p53在镍诱导的转化中的作用，我们使用人骨肉瘤（HOS）细胞和镍转化的衍生物SA-8细胞。由于非功能性p53在HOS和SA-8细胞中表达，急性Ni处理诱导HIF-1 α蛋白和HIF-1依赖性转录而不影响p53。在MCF-7和A549中，具有野生型p53的人癌细胞，在暴露于Ni后，功能性p53和HIF-1 α蛋白都积累。Ni对HIF-1 α和野生型p53的诱导在6小时后检测到，并且在24小时时最明显。这些结果表明，急性Ni处理导致HIF-1 α蛋白积累和野生型p53的同时积累。而不是突变型p53。我们认为，镍处理的细胞与随后的选择增加HIF-1依赖的转录缺氧样条件的诱导参与镍诱导的致癌作用。
Nickel (Ni) compounds are potent carcinogens and can induce malignant transformation of rodent and human cells. In an attempt to unravel the molecular mechanisms of Ni-induced transformation we investigated transcriptional activity of hypoxia-inducible factor (HIF-1) and p53 tumor suppressor protein in Ni-transformed cells, We demonstrated that the activity of HIF-1-responsive promoters was increased in Ni-transformed rodent cells resulting in the increased ratio between HIF-1- and p53-stimulated transcription. To further elucidate the roles of HIF-1 and p53 in Ni-induced transformation we used human osteosarcoma (HOS) cells and a Ni-transformed derivative, SA-8 cells. Since non-functional p53 was expressed in both HOS and SA-8 cells, acute Ni treatment induced HIF-1 alpha protein and HIF-1-dependent transcription without affecting p53. In MCF-7 and A549, human cancer cells with the wild-type p53, both functional p53 and HIF-1 alpha proteins accumulated following exposure to Ni, The induction of HIF-1 alpha and wild-type p53 by Ni was detected after 6 h and was most pronounced by 24 h, These results suggest that acute Ni treatment causes accumulation of HIF-1 alpha protein and simultaneous accumulation of wild-type, but not mutant, p53. We suggest that the induction of hypoxia-like conditions in Ni-treated cells with subsequent selection for increased HIF-1-dependent transcription is involved in Ni-induced carcinogenesis.