Distinct regulatory mechanisms of the human ferritin gene by hypoxia and hypoxia mimetic cobalt chloride at the transcriptional and post-transcriptional levels.
Distinct regulatory mechanisms of the human ferritin gene by hypoxia and hypoxia mimetic cobalt chloride at the transcriptional and post-transcriptional levels.
复制标题
DOI：
10.1016/j.cellsig.2014.08.018
复制
发表时间：
2014-12
影响因子：
4.8
通讯作者：
Tsuji Y
中科院分区：
文献类型：
--
作者：
Huang BW;Miyazawa M;Tsuji Y
氯化钴已被用作缺氧模拟物，因为它可以稳定缺氧诱导因子 1α (HIF1-α)，并通过缺氧反应元件 (HRE) 激活基因转录。然而，缺氧和模拟缺氧氯化钴在基因调控方面的差异仍然难以捉摸。铁蛋白（主要的铁储存蛋白）的表达通过 DNA 和 RNA 调节元件在转录和转录后水平上受到调节。在这里，我们证明缺氧和氯化钴通过两种不同的机制调节铁蛋白重链（铁蛋白 H）的表达。缺氧和氯化钴都会增加 HIF1-α，但人铁蛋白 H 基因中假定的 HRE 并未激活。相反，氯化钴而非缺氧通过抗氧化反应元件（ARE）激活铁蛋白 H 转录，Nrf2 被招募到该元件中。有趣的是，氯化钴下调了 K562 细胞中铁蛋白 H 蛋白的表达，同时上调了其他 ARE 调节的抗氧化基因。进一步的表征表明，氯化钴增加了铁调节蛋白（IRP1 和 IRP2）与铁蛋白 H mRNA 5'UTR 中铁反应元件 (IRE) 之间的相互作用，从而导致积累的铁蛋白 H mRNA 的翻译受阻。相反，缺氧对铁蛋白 H 转录有边际影响，但通过减少 IRP1-IRE 相互作用而增加其翻译。这些结果表明，缺氧和模拟缺氧氯化钴通过 DNA 和 mRNA 元件在转录和转录后水平上的相互作用采用不同的调节机制。
Cobalt chloride has been used as a hypoxia mimetic because it stabilizes hypoxia inducible factor-1α (HIF1-α) and activates gene transcription through a hypoxia responsive element (HRE). However, differences between hypoxia and hypoxia mimetic cobalt chloride in gene regulation remain elusive. Expression of ferritin, the major iron storage protein, is regulated at the transcriptional and posttranscriptional levels through DNA and RNA regulatory elements. Here we demonstrate that hypoxia and cobalt chloride regulate ferritin heavy chain (ferritin H) expression by two distinct mechanisms. Both hypoxia and cobalt chloride increased HIF1-α but a putative HRE in the human ferritin H gene was not activated. Instead, cobalt chloride but not hypoxia activated ferritin H transcription through an antioxidant responsive element (ARE), to which Nrf2 was recruited. Intriguingly, cobalt chloride downregulated ferritin H protein expression while upregulated other ARE-regulated antioxidant genes in K562 cells. Further characterization demonstrated that cobalt chloride increased interaction between iron regulatory proteins (IRP1 and IRP2) and iron responsive element (IRE) in the 5′UTR of ferritin H mRNA, resulting in translational block of the accumulated ferritin H mRNA. In contrast, hypoxia had marginal effect on ferritin H transcription but increased its translation through decreased IRP1-IRE interaction. These results suggest that hypoxia and hypoxia mimetic cobalt chloride employ distinct regulatory mechanisms through the interplay between DNA and mRNA elements at the transcriptional and post-transcriptional levels.
登录
查看更多内容
白藜芦醇在人类T细胞中，AMP激活的蛋白激酶在铁蛋白H基因表达中的作用。
影响因子：
2.9
作者：
Iwasaki, Kenta;Ray, Paul D.;Huang, Bo-Wen;Sakamoto, Kensuke;Kobayashi, Takaaki;Tsuji, Yoshiaki
通讯作者：
Tsuji, Yoshiaki
影响因子：
14.9
作者：
Chorley BN;Campbell MR;Wang X;Karaca M;Sambandan D;Bangura F;Xue P;Pi J;Kleeberger SR;Bell DA
通讯作者：
Bell DA
影响因子：
4.8
作者：
Hanson, ES;Foot, LM;Leibold, EA
通讯作者：
Leibold, EA
影响因子：
4.8
作者：
Pietsch, EC;Chan, JY;Torti, SV
通讯作者：
Torti, SV
影响因子：
4.8
作者：
Huang, Bo-Wen;Ray, Paul D.;Tsuji, Yoshiaki
通讯作者：
Tsuji, Yoshiaki