Bisphenol A, an environmental endocrine-disrupting chemical, inhibits hypoxic response via degradation of hypoxia-inducible factor 1α (HIF-1α): structural requirement of bisphenol A for degradation of HIF-1α
Bisphenol A, an environmental endocrine-disrupting chemical, inhibits hypoxic response via degradation of hypoxia-inducible factor 1α (HIF-1α): structural requirement of bisphenol A for degradation of HIF-1α
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DOI：
10.1016/j.bbrc.2004.04.125
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发表时间：
2004-06
影响因子：
3.1
通讯作者：
T. Kubo;Nobuhiro Maezawa;Mayuko Osada;S. Katsumura;Y. Funae;S. Imaoka
中科院分区：
文献类型：
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作者：
T. Kubo;Nobuhiro Maezawa;Mayuko Osada;S. Katsumura;Y. Funae;S. Imaoka
双酚A（BpA）是一种内分泌干扰化学物质，已知是一种异种雌激素，会影响动物的生殖功能。最近的报告已经记录了BPA诱导的人类和动物神经系统发育异常，这些影响似乎是非雌激素性的。在本研究中，我们发现BpA抑制人肝癌细胞的缺氧反应。低氧应答基因如促红细胞生成素（EPO）基因的表达通过低氧诱导因子1（HIF-1）依赖性信号传导途径完成。为了研究这种抑制作用的可能结构要求，合成了几种BpA类似物并加入到该系统中。封闭BpA中的两个酚基并不改变该效应，但通过去除BpA中的两个中心甲基（所得化合物被指定为BpF），抑制作用完全消失。BpA而不是BpF促进HIF-1α蛋白的降解，HIF-1α蛋白是HIF-1的组分，随后抑制EPO诱导。免疫沉淀实验表明BpA可使HIF-1α与热休克蛋白90（Hsp 90）解离，使HIF-1α蛋白失稳。HIF-1α通常首先通过泛素化降解，然后通过蛋白酶体途径降解。钴离子抑制HIF-1α的泛素化并使其稳定，在本研究中，BpA在钴离子和蛋白酶体抑制剂的存在下促进HIF-1α的降解。这些结果表明BpA通过目前未知的途径降解HIF-1α，并且这种现象需要BpA中的两个甲基。
Bisphenol A (BpA), an endocrine-disrupting chemical, is known to be a xenoestrogen and to affect the reproductive functions of animals. Recent reports have documented BpA-induced developmental abnormalities in the neuronal systems of humans and animals, and these effects appear to be non-estrogenic. In this study, we found that BpA inhibited the hypoxic response of human hepatoma cells. The expression of hypoxic response genes such as the erythropoietin (EPO) gene is done via a hypoxia inducible factor 1 (HIF-1)-dependent signaling pathway. To investigate possible structural requirements for this inhibitory effect, several BpA analogs were synthesized and added to this system. The blocking of two phenol groups in BpA did not change the effect, but the inhibition completely disappeared by the removal of two central methyl groups in BpA (the resulting compound is designated BpF). BpA, but not BpF, promoted degradation of the HIF-1α protein, which is a component of HIF-1, followed by inhibition of EPO induction. An immunoprecipitation assay indicated that BpA dissociated heat shock protein 90 (Hsp90) from HIF-1α and destabilized HIF-1α protein. HIF-1α is usually degraded first by ubiquitination and then by the proteasome pathway. Cobalt ion inhibits ubiquitination of HIF-1α and stabilizes it. In the present study, BpA promoted HIF-1α degradation in the presence of cobalt and in the presence of proteasome inhibitor. These results suggest that BpA degraded HIF-1α via a currently unknown pathway, and that this phenomenon required two methyl groups in BpA.