Identification and mechanistic characterization of low-molecular-weight inhibitors for HuR
| Autor: | Maximilian Woisetschlaeger, Kurt Mueller, Roman Bauer, Lukas Oberer, Johannes Ottl, Nathalie Harrer, Jan-Marcus Seifert, Volker Uhl, Christian Guenat, Martin Hintersteiner, Manfred Auer, Christof Buehler, Serge Moss, Nicole-Claudia Meisner, Hans-Ulrich Naegeli |
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| Rok vydání: | 2007 |
| Předmět: |
Molecular Sequence Data
HU Protein Drug Evaluation Preclinical ELAV-Like Protein 1 Fluorescence Polarization Naphthols Biology Binding Competitive Anti-Infective Agents Actinomyces Humans Furans Molecular Biology Anthracenes Messenger RNA Dose-Response Relationship Drug Drug discovery RNA-Binding Proteins RNA Cell Biology Models Theoretical Kinetics ELAV Proteins Structural biology Biochemistry Pyrones Drug Design Antigens Surface Signal transduction Functional genomics |
| Zdroj: | Nature Chemical Biology. 3:508-515 |
| ISSN: | 1552-4469 1552-4450 |
| DOI: | 10.1038/nchembio.2007.14 |
| Popis: | Careful regulation of mRNA half-lives is a fundamental mechanism allowing cells to quickly respond to changing environmental conditions. The mRNA-binding Hu proteins are important for stabilization of short-lived mRNAs. Here we describe the identification and mechanistic characterization of the first low-molecular-weight inhibitors for Hu protein R (HuR) from microbial broths (Actinomyces sp.): dehydromutactin (1), MS-444 (2) and okicenone (3). These compounds interfere with HuR RNA binding, HuR trafficking, cytokine expression and T-cell activation. A mathematical and experimental analysis of the compounds' mode of action suggests that HuR homodimerizes before RNA binding and that the compounds interfere with the formation of HuR dimers. Our results demonstrate the chemical drugability of HuR; to our knowledge HuR is the first example of a drugable protein within the Hu family. MS-444, dehydromutactin and okicenone may become valuable tools for studying HuR function. An assessment of HuR inhibition as a central node in malignant processes might open up new conceptual routes toward combatting cancer. |
| Databáze: | OpenAIRE |
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