Suppr超能文献

锌原卟啉对血红素加氧酶-1诱导和细胞凋亡的独特作用。

Unique effects of zinc protoporphyrin on HO-1 induction and apoptosis.

作者信息

Yang G, Nguyen X, Ou J, Rekulapelli P, Stevenson D K, Dennery P A

机构信息

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305 USA.

出版信息

Blood. 2001 Mar 1;97(5):1306-13. doi: 10.1182/blood.v97.5.1306.

Abstract

Zinc protoporphyrin (ZnPP), a naturally occurring molecule, is increased in iron deficiency and lead intoxication. ZnPP can also induce heme oxygenase (HO-1), the enzyme it competitively inhibits. In cultured cells (HA-1), ZnPP was the strongest HO-1 inducer of any metalloporphyrin (MP) tested. This was not due to increased oxidative stress, enhanced binding at metal response element, nor increased binding at activator protein-1 (AP-1) or SP-1 sites on HO-1. Only ZnPP, however, increased binding of nuclear proteins to early growth response-1 (Egr-1) protein consensus sequence. Pretreatment of HA-1 with cycloheximide inhibited ZnPP-induced HO-1 messenger RNA (mRNA) by 55%. Incubation with antisense Egr-1 oligomers decreased ZnPP-induced HO-1 expression by 47%. Furthermore, the level of HO-1 mRNA induction by ZnPP was 2-fold less in Egr-1-deficient fibroblasts than in wild-type cells. Because no Egr-1 binding site was previously identified on the HO-1 promoter, HA-1 cells were transfected with HO-1 CAT constructs containing segments of a 12.5-kb enhancer region of HO-1. A 196-bp fragment (RH) located approximately 9.5 kb upstream of the transcription start site mediated HO-1 induction by ZnPP alone. DNase I footprinting analysis further revealed that nuclear proteins bound to a 50-bp sequence in the RH. Within this sequence, a novel 9-bp region with 78% homology to the Egr-1 consensus sequence was identified further suggesting that Egr-1 partially mediates HO-1 induction by ZnPP. Lastly, increased apoptosis and nuclear localization were only seen with ZnPP, suggesting that increased ZnPP in disease states may serve as a cellular signaling mechanism.

摘要

锌原卟啉(ZnPP)是一种天然存在的分子,在缺铁和铅中毒时会增加。ZnPP还能诱导血红素加氧酶(HO-1),而它会竞争性抑制这种酶。在培养细胞(HA-1)中,ZnPP是所测试的任何金属卟啉(MP)中最强的HO-1诱导剂。这并非由于氧化应激增加、在金属反应元件上的结合增强,也不是由于在HO-1的激活蛋白-1(AP-1)或SP-1位点上的结合增加。然而,只有ZnPP增加了核蛋白与早期生长反应-1(Egr-1)蛋白共有序列的结合。用环己酰亚胺预处理HA-1可使ZnPP诱导的HO-1信使核糖核酸(mRNA)减少55%。用反义Egr-1寡聚物孵育可使ZnPP诱导的HO-1表达减少47%。此外,在Egr-1缺陷的成纤维细胞中,ZnPP诱导的HO-1 mRNA水平比野生型细胞低2倍。由于之前在HO-1启动子上未鉴定出Egr-1结合位点,因此用含有HO-1 12.5 kb增强子区域片段的HO-1 CAT构建体转染HA-1细胞。位于转录起始位点上游约9.5 kb处的一个196 bp片段(RH)单独介导了ZnPP对HO-1的诱导。脱氧核糖核酸酶I足迹分析进一步显示,核蛋白与RH中的一个50 bp序列结合。在这个序列中,鉴定出一个与Egr-1共有序列有78%同源性的新的9 bp区域,进一步表明Egr-1部分介导了ZnPP对HO-1的诱导。最后,只有ZnPP能观察到凋亡增加和核定位,这表明疾病状态下ZnPP增加可能作为一种细胞信号机制。

文献检索

告别复杂PubMed语法,用中文像聊天一样搜索,搜遍4000万医学文献。AI智能推荐,让科研检索更轻松。

立即免费搜索

文件翻译

保留排版,准确专业,支持PDF/Word/PPT等文件格式,支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述,25分钟生成高质量综述,智能提取关键信息,辅助科研写作。

立即免费体验