Cobalt stimulates HIF-1-dependent but inhibits HIF-2-dependent gene expression in liver cancer cells.
Cobalt stimulates HIF-1-dependent but inhibits HIF-2-dependent gene expression in liver cancer cells.
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钴刺激HIF-1依赖性，但抑制肝癌细胞中HIF-2依赖性基因表达。
DOI：
10.1016/j.biocel.2013.07.025
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发表时间：
2013-11
影响因子：
4
通讯作者：
Liakos, Panagiotis
中科院分区：
文献类型：
--
作者：
Befani, Christina;Mylonis, Ilias;Gkotinakou, Ioanna-Maria;Georgoulias, Panagiotis;Hu, Cheng-Jun;Simos, George;Liakos, Panagiotis
低氧诱导因子（HIF）是介导细胞对低氧反应的转录调节因子。虽然HIF-1通常被认为是低氧适应的主要介质，但在低氧下或当用低氧模拟化学品如钴处理时，几种组织和不同的细胞类型表达HIF-1和HIF-2同种型。然而，HIF-1和HIF-2之间的相似性或差异，在其组织和诱导剂特异性激活和功能方面，没有得到充分的表征。为了解决这个问题，我们研究了真正的缺氧和缺氧模拟物对HIF-1和HIF-2的诱导和特定的基因转录活性在两个肝癌细胞系，Huh 7和HepG 2的影响。缺氧和钴均能引起HIF-1α和HIF-2α蛋白的快速诱导。缺氧诱导促红细胞生成素（EPO）的表达和分泌的HIF-2依赖的方式。然而，令人惊讶的是，当用钴处理细胞时，EPO表达没有被诱导。一致的是，HIF-1和HIF-2依赖性启动子（分别为PGK和SOD 2基因）被缺氧激活，而钴仅激活HIF-1依赖性PGK启动子。与钴不同，其他低氧模拟物如DFO和DMOG激活两种类型的启动子。此外，钴削弱了低氧刺激的HIF-2，但不是HIF-1，活性和钴诱导的HIF-2α与USF-2，HIF-2特异性的辅激活剂相互作用差。这些数据表明，尽管HIF-1α和HIF-2α蛋白表达的诱导相似，但HIF-1和HIF-2特异性基因激活功能对不同刺激的反应不同，并表明涉及额外转录因子或共激活因子的氧非依赖性和基因或组织特异性调节机制的运作。
Hypoxia-inducible factors (HIFs) are transcriptional regulators that mediate the cellular response to low oxygen. Although HIF-1 is usually considered as the principal mediator of hypoxic adaptation, several tissues and different cell types express both HIF-1 and HIF-2 isoforms under hypoxia or when treated with hypoxia mimetic chemicals such as cobalt. However, the similarities or differences between HIF-1 and HIF-2, in terms of their tissue- and inducer-specific activation and function, are not adequately characterized. To address this issue, we investigated the effects of true hypoxia and hypoxia mimetics on HIF-1 and HIF-2 induction and specific gene transcriptional activity in two hepatic cancer cell lines, Huh7 and HepG2. Both hypoxia and cobalt caused rapid induction of both HIF-1α and HIF-2α proteins. Hypoxia induced erythropoietin (EPO) expression and secretion in a HIF-2-dependent way. Surprisingly, however, EPO expression was not induced when cells were treated with cobalt. In agreement, both HIF-1- and HIF-2-dependent promoters (of PGK and SOD2 genes, respectively) were activated by hypoxia while cobalt only activated the HIF-1-dependent PGK promoter. Unlike cobalt, other hypoxia mimetics such as DFO and DMOG activated both types of promoters. Furthermore, cobalt impaired the hypoxic stimulation of HIF-2, but not HIF-1, activity and cobalt-induced HIF-2α interacted poorly with USF-2, a HIF-2-specific co-activator. These data show that, despite similar induction of HIF-1α and HIF-2α protein expression, HIF-1 and HIF-2 specific gene activating functions respond differently to different stimuli and suggest the operation of oxygen-independent and gene- or tissue-specific regulatory mechanisms involving additional transcription factors or co-activators.
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影响因子：
11.2
作者：
Aprelikova, Olga;Wood, Matthew;Barrett, J. Carl
通讯作者：
Barrett, J. Carl
影响因子：
4.7
作者：
Befani, Christina D.;Vlachostergios, Panagiotis J.;Liakos, Panagiotis
通讯作者：
Liakos, Panagiotis
影响因子：
4
作者：
Kalousi, Alkmini;Mylonis, Ilias;Simos, George
通讯作者：
Simos, George
影响因子：
4
作者：
Mylonis, Ilias;Sembongi, Hiroshi;Simos, George
通讯作者：
Simos, George
影响因子：
5.3
作者：
Chavez, Juan C.;Baranova, Oxana;Pichiule, Paola
通讯作者：
Pichiule, Paola