A screening strategy for the discovery of drugs that reduce C/EBPβ-LIP translation with potential calorie restriction mimetic properties
| العنوان: | A screening strategy for the discovery of drugs that reduce C/EBPβ-LIP translation with potential calorie restriction mimetic properties |
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| المؤلفون: | Mohamad A. Zaini, Jeanette Reinshagen, Tobias Ackermann, Cornelis F. Calkhoven, Ole Pless, Gertrud Kortman, Christine Müller |
| المساهمون: | Publica |
| المصدر: | Scientific Reports Scientific Reports, 7:42603. Nature Publishing Group |
| بيانات النشر: | Nature Publishing Group, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, EXPRESSION, Calorie restriction, Genetic Vectors, PROTEIN, Gene Expression, RE-INITIATION, mTORC1, Biology, Article, Cell Line, CONTROL REPORTER SYSTEM, 03 medical and health sciences, Genes, Reporter, Enhancer binding, Upstream open reading frame, Drug Discovery, Gene Order, Protein biosynthesis, Humans, RNA, Messenger, Transcription factor, IMPROVES METABOLIC HEALTH, Caloric Restriction, Regulation of gene expression, Multidisciplinary, MTOR INHIBITORS, CCAAT-Enhancer-Binding Protein-beta, Reproducibility of Results, Translation (biology), CANCER, Cell biology, High-Throughput Screening Assays, MICE, stomatognathic diseases, 030104 developmental biology, Biochemistry, Gene Expression Regulation, MAMMALIAN LIFE-SPAN, Protein Biosynthesis, MESSENGER-RNA |
| الوصف: | An important part of the beneficial effects of calorie restriction (CR) on healthspan and lifespan is mediated through regulation of protein synthesis that is under control of the mechanistic target of rapamycin complex 1 (mTORC1). As one of its activities, mTORC1 stimulates translation into the metabolic transcription factor CCAAT/Enhancer Binding Protein β (C/EBPβ) isoform Liver-specific Inhibitory Protein (LIP). Regulation of LIP expression strictly depends on a translation re-initiation event that requires a conserved cis-regulatory upstream open reading frame (uORF) in the C/EBPβ-mRNA. We showed before that suppression of LIP in mice, reflecting reduced mTORC1-signaling at the C/EBPβ level, results in CR-type of metabolic improvements. Hence, we aim to find possibilities to pharmacologically down-regulate LIP in order to induce CR-mimetic effects. We engineered a luciferase-based cellular reporter system that acts as a surrogate for C/EBPβ-mRNA translation, emulating uORF-dependent C/EBPβ-LIP expression under different translational conditions. By using the reporter system in a high-throughput screening (HTS) strategy we identified drugs that reduce LIP. The drug Adefovir Dipivoxil passed all counter assays and increases fatty acid β-oxidation in a hepatoma cell line in a LIP-dependent manner. Therefore, these drugs that suppress translation into LIP potentially exhibit CR-mimetic properties. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2045-2322 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::05625b2186ea195c2e46c4118f18ee97Test http://europepmc.org/articles/PMC5309760Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....05625b2186ea195c2e46c4118f18ee97 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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