Regulation of hypoxia-inducible genes by ETS1 transcription factor
Regulation of hypoxia-inducible genes by ETS1 transcription factor
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DOI：
10.1093/carcin/bgn088
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发表时间：
2008-08-01
期刊：
影响因子：
4.7
通讯作者：
Niederhuber, John
中科院分区：
文献类型：
--
作者：
Salnikow, Konstantin;Aprelikova, Olga;Niederhuber, John
缺氧诱导因子（HIF-1）通过使肿瘤细胞对治疗干预更具抗性来调节促进肿瘤细胞存活的基因的表达。最近的证据表明，其他转录因子的激活，与HIF-1合作或单独作用，参与了缺氧诱导基因的上调。在这里，我们报告说，高细胞密度，一个条件，可能模仿生长肿瘤的生理情况，最有可能代表营养饥饿，上调缺氧诱导基因。这种上调可以以HIF非依赖性方式发生，因为低氧诱导基因碳酸酐酶9（CA 9）、赖氨酰氧化酶样2（L0 XL 2）和n-myc下调1（NDRG 1）/钙激活蛋白（Cap 43）可以通过在常氧和低氧条件下在HIF-1 α熟练和缺乏的小鼠成纤维细胞中增加细胞密度而上调。此外，细胞密度上调1HAEo-和A549人肺上皮细胞中的相同基因。寻找其他参与细胞密度对低氧诱导基因调控的转录因子，我们将注意力集中在ETS 1上。如前所述，成红细胞增多症病毒E26癌基因同源物（ETS）家族转录因子的成员参与低氧诱导基因的上调。在这里，我们提供的证据表明，ETS 1蛋白在人类和小鼠细胞的高细胞密度上调。ETS 1参与低氧诱导基因的上调，进一步证实了在荧光素酶报告基因测定使用共转染ETS 1表达载体NDRG 1/Cap 43启动子构建体。用小干扰RNA（siRNA）下调ETS 1表达可抑制细胞密度增加引起的CA 9和NDRG 1/Cap 43的上调。总的来说，我们的数据表明参与ETS 1沿着与HIF-1在调节缺氧诱导基因。
Hypoxia-inducible factor (HIF-1) regulates the expression of genes that facilitate tumor cell survival by making them more resistant to therapeutic intervention. Recent evidence suggests that the activation of other transcription factors, in cooperation with HIF-1 or acting alone, is involved in the upregulation of hypoxia-inducible genes. Here we report that high cell density, a condition that might mimic the physiologic situation in growing tumor and most probably representing nutritional starvation, upregulates hypoxia-inducible genes. This upregulation can occur in HIF-independent manner since hypoxia-inducible genes carbonic anhydrase 9 (CA9), lysyloxidase like 2 (LOXL2) and n-myc-down regulated 1 (NDRG1)/calcium activated protein (Cap43) can be upregulated by increased cell density under both normoxic and hypoxic conditions in both HIF-1 alpha-proficient and -deficient mouse fibroblasts. Moreover, cell density upregulates the same genes in 1HAEo- and A549 human lung epithelial cells. Searching for other transcription factors involved in the regulation of hypoxia-inducible genes by cell density, we focused our attention on ETS1. As reported previously, members of v-ets erythroblastosis virus E26 oncogene homolog (ETS) family transcription factors participate in the upregulation of hypoxia-inducible genes. Here, we provide evidence that ETS1 protein is upregulated at high cell density in both human and mouse cells. The involvement of ETS1 in the upregulation of hypoxia-inducible genes was further confirmed in a luciferase reporter assay using cotransfection of ETS1 expression vector with NDRG1/Cap43 promoter construct. The downregulation of ETS1 expression with small interfering RNA (siRNA) inhibited the upregulation of CA9 and NDRG1/Cap43caused by increased cell density. Collectively, our data indicate the involvement of ETS1 along with HIF-1 in regulating hypoxia-inducible genes.