Intermedin/adrenomedullin 2 is a stress-inducible gene controlled by activating transcription factor 4
Intermedin/adrenomedullin 2 is a stress-inducible gene controlled by activating transcription factor 4
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DOI：
10.1016/j.gene.2016.06.037
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发表时间：
2016-09-15
期刊：
影响因子：
3.5
通讯作者：
Evstafieva, Alexandra G.
中科院分区：
文献类型：
--
作者：
Kovaleva, Irina E.;Garaeva, Alisa A.;Evstafieva, Alexandra G.
Intermedin或肾上腺髓质素2是一组具有推定的肿瘤血管生成促进活性的降钙素相关肽，其通过ADM 2基因产物的蛋白水解加工形成。已经提出ADM 2基因受在其启动子区域内发现的雌激素反应元件（ERE）和缺氧反应元件（HRE）调节。本研究揭示了ADM 2参与未折叠蛋白反应（UPR）和线粒体呼吸链抑制反应的功能机制。我们表明，ADM 2基因是由激活转录因子4（ATF 4），综合应激反应（ISR）的主要调节器。药物ISR抑制剂ISRIB和特异性shRNA下调ATF 4可抑制ADM 2 mRNA的上调，而ATF 4 cDNA的异位表达导致ADM 2基因转录的显著增加。在ADM 2基因的编码区中鉴定了一个潜在的ATF 4结合位点，并通过荧光素酶报告基因测定验证了ATF 4介导的ADM 2基因启动子激活期间对该位点的需求。推定的ATF 4-响应元件的突变防止响应于ATF 4过量产生的荧光素酶活性的诱导，以及响应于由杀粉蝶菌素A引起的线粒体电子转移链抑制和由衣霉素和布雷菲德菌素A引起的ER应激诱导。由于ADM 2在心肌ER应激过程中抑制ATF 4表达，因此可以提出ER应激条件下ADM 2调节的反馈机制。(C)2016爱思唯尔B. V.保留所有权利。
Intermedin or adrenomedullin 2 is a set of calcitonin-related peptides with a putative tumor angiogenesis promoting activity that are formed by proteolytic processing of the ADM2 gene product. It has been proposed that the ADM2 gene is regulated by the estrogen response element (ERE) and hypoxia response elements (HRE) found within its promoter region. In the present study we reveal a functional mechanism by which ADM2 participates in the unfolded protein response (UPR) and in responses to the mitochondrial respiration chain inhibition. We show that the ADM2 gene is controlled by activating transcription factor 4 (ATF4), the principal regulator of the integrated stress response (ISR). The upregulation of ADM2 mRNA could be prevented by the pharmacological ISR inhibitor ISRIB and by the downregulation of ATF4 with specific shRNA, while ectopic expression of ATF4 cDNA resulted in a notable increase in ADM2 gene transcription. A potential ATF4-binding site was identified in the coding region of the ADM2 gene and the requirement of this site during the ATF4-mediated ADM2 gene promoter activation was validated by the luciferase reporter assay. Mutagenesis of the putative ATF4-response element prevented the induction of luciferase activity in response to ATF4 overproduction, as well as in response to mitochondrial electron transfer chain inhibition by piericidin A and ER stress induction by tunicamycin and brefeldin A. Since ADM2 was shown to inhibit ATF4 expression during myocardial ER stress, a feedback mechanism could be proposed for the ADM2 regulation under ER stress conditions. (C) 2016 Elsevier B.V. All rights reserved.