title: Up-regulation of c-Jun N-terminal kinase pathway in Friedreich's ataxia cells.
abstract: The severe reduction in mRNA and protein levels of the mitochondrial protein frataxin, encoded by the X25 gene, causes Friedreich ataxia (FRDA), the most common form of recessive hereditary ataxia. Increasing evidence underlines the pathogenetic role of oxidative stress in this disease. We generated an in vitro cellular model of regulated human frataxin overexpression. We identified, by differential display technique, the mitogen activated protein kinase kinase 4 mRNA down regulation in frataxin overexpressing cells. We studied the stress kinases pathway in this cellular model and in fibroblasts from FRDA patients. Frataxin overexpression reduced c-Jun N-terminal kinase phosphorylation. Furthermore, exposure of FRDA fibroblasts to several forms of environmental stress caused an up regulation of phospho-JNK and phospho-c-Jun. To understand if this susceptibility results in cell death, we have investigated the involvement of caspases. A significantly higher activation of caspase-9 was observed in FRDA versus control fibroblasts after serum-withdrawal. Our findings suggest the presence, in FRDA patient cells, of a 'hyperactive' stress signaling pathway. The role of frataxin in FRDA pathogenesis could be explained, at least in part, by this hyperactivity.
authors.affiliation: BioGeM Consortium and Department of Molecular and Cellular Biology and Pathology and IEOS, CNR, Federico II University, Naples, Italy. pianese@biogem.it
authors.forename: Luigi
authors.initials: L
authors.lastname: Pianese
authors.forename: Luca
authors.initials: L
authors.lastname: Busino
authors.forename: Irene
authors.initials: I
authors.lastname: De Biase
authors.forename: Tiziana
authors.initials: T
authors.lastname: De Cristofaro
authors.forename: Maria S
authors.initials: MS
authors.lastname: Lo Casale
authors.forename: Paola
authors.initials: P
authors.lastname: Giuliano
authors.forename: Antonella
authors.initials: A
authors.lastname: Monticelli
authors.forename: Mimmo
authors.initials: M
authors.lastname: Turano
authors.forename: Chiara
authors.initials: C
authors.lastname: Criscuolo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Filla
authors.forename: Stelio
authors.initials: S
authors.lastname: Varrone
authors.forename: Sergio
authors.initials: S
authors.lastname: Cocozza
mesh_terms: D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology; D005621:Friedreich Ataxia / Q000201:enzymology* / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D033862:Iron-Binding Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress; D016716:PC12 Cells; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D051381:Rats; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation; D000096923:Frataxin
chemical_list: D053453:Caspase 9; D020169:Caspases; D006861:Hydrogen Peroxide; D033862:Iron-Binding Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D000096923:Frataxin; C482559:MAP2K4 protein, human; C506433:CASP9 protein, human; C506435:Casp9 protein, rat