Src inhibitors modulate frataxin protein levels
| Autor: | Marco Crescenzi, Ivano Condò, Ilaria Guccini, Alessandra Rufini, Silvia Fortuni, Florence Malisan, Gaetano Arcuri, Shadman Moiz, Serena Camerini, Dario Serio, Fabio Cherubini, Roberto Testi |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Regulation of gene expression
Settore MED/04 - Patologia Generale biology Ubiquitination Iron-binding proteins General Medicine Aconitase Adenosine Triphosphate src-Family Kinases Gene Expression Regulation Ubiquitin Friedreich Ataxia Iron-Binding Proteins Genetics Frataxin biology.protein Cancer research Humans Phosphorylation Enzyme Inhibitors Oxidation-Reduction Molecular Biology Tyrosine kinase Genetics (clinical) Proto-oncogene tyrosine-protein kinase Src |
| Popis: | Defective expression of frataxin is responsible for the inherited, progressive degenerative disease Friedreich's Ataxia (FRDA). There is currently no effective approved treatment for FRDA and patients die prematurely. Defective frataxin expression causes critical metabolic changes, including redox imbalance and ATP deficiency. As these alterations are known to regulate the tyrosine kinase Src, we investigated whether Src might in turn affect frataxin expression. We found that frataxin can be phosphorylated by Src. Phosphorylation occurs primarily on Y118 and promotes frataxin ubiquitination, a signal for degradation. Accordingly, Src inhibitors induce accumulation of frataxin but are ineffective on a non-phosphorylatable frataxin-Y118F mutant. Importantly, all the Src inhibitors tested, some of them already in the clinic, increase frataxin expression and rescue the aconitase defect in frataxin-deficient cells derived from FRDA patients. Thus, Src inhibitors emerge as a new class of drugs able to promote frataxin accumulation, suggesting their possible use as therapeutics in FRDA. |
| Databáze: | OpenAIRE |
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