title: Src inhibitors modulate frataxin protein levels.
abstract: 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.
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Cherubini
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Serio
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Guccini
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy, Fratagene Therapeutics Ltd, 22 Northumberland Rd, Dublin, Ireland and.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fortuni
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Arcuri
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Ivano
authors.initials: I
authors.lastname: Condò
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy, Fratagene Therapeutics Ltd, 22 Northumberland Rd, Dublin, Ireland and.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rufini
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Shadman
authors.initials: S
authors.lastname: Moiz
authors.affiliation: Department of Cell Biology and Neurosciences, Italian National Institute of Health, Viale Regina Elena, 299, 00161 Rome, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Camerini
authors.affiliation: Department of Cell Biology and Neurosciences, Italian National Institute of Health, Viale Regina Elena, 299, 00161 Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Crescenzi
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy, Fratagene Therapeutics Ltd, 22 Northumberland Rd, Dublin, Ireland and.
authors.forename: Roberto
authors.initials: R
authors.lastname: Testi
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy, malisan@med.uniroma2.it.
authors.forename: Florence
authors.initials: F
authors.lastname: Malisan
mesh_terms: D000255:Adenosine Triphosphate / Q000172:deficiency / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005621:Friedreich Ataxia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D033862:Iron-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D010084:Oxidation-Reduction; D054875:Ubiquitination / Q000235:genetics; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000096923:Frataxin
chemical_list: D000255:Adenosine Triphosphate; D004791:Enzyme Inhibitors; D033862:Iron-Binding Proteins; D019061:src-Family Kinases; D000096923:Frataxin