Intermedin/adrenomedullin 2 is a stress-inducible gene controlled by activating transcription factor 4

• Published in: Gene 2016-09, Vol.590 (1), p.177-185
• Main Authors: Kovaleva, Irina E., Garaeva, Alisa A., Chumakov, Peter M., Evstafieva, Alexandra G.
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 4 - antagonists & inhibitors; Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Angiogenesis; Binding Sites; Brefeldin A - pharmacology; Electron Transport Complex III - antagonists & inhibitors; Electron Transport Complex III - genetics; Electron Transport Complex III - metabolism; Feedback, Physiological; Gene Expression Regulation; Gene Ontology; HCT116 Cells; HeLa Cells; Humans; Integrated stress response; Intermedin/adrenomedullin 2; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial respiratory chain complex; Molecular Sequence Annotation; Peptide Hormones - chemistry; Peptide Hormones - genetics; Peptide Hormones - metabolism; Plasmids - chemistry; Plasmids - metabolism; Protein Binding; Pyridines - pharmacology; Response Elements; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; Transcription factor ATF4; Transcription, Genetic; Tumor suppressor p53; Tunicamycin - pharmacology; Unfolded Protein Response
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2016.06.037

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. •ADM2 gene expression is induced in response to mitochondrial respiration chain inhibition.•ADM2 is regulated by transcription factor ATF4 during the integrated stress response.•ATF4-response element is located in the coding region of ADM2 gene.•ATF4 contributes to ADM2 promoter induction in response to ER stress.•ADM2 is included in the set of proangiogenic genes up-regulated in the course of ISR.