RGD Reference Report - Dual role of the mitochondrial protein frataxin in astrocytic tumors. - Rat Genome Database

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Dual role of the mitochondrial protein frataxin in astrocytic tumors.

Authors: Kirches, Elmar  Andrae, Nadine  Hoefer, Aline  Kehler, Barbara  Zarse, Kim  Leverkus, Martin  Keilhoff, Gerburg  Schonfeld, Peter  Schneider, Thomas  Wilisch-Neumann, Annette  Mawrin, Christian 
Citation: Kirches E, etal., Lab Invest. 2011 Dec;91(12):1766-76. doi: 10.1038/labinvest.2011.130. Epub 2011 Aug 22.
RGD ID: 401793715
Pubmed: PMID:21863062   (View Abstract at PubMed)
DOI: DOI:10.1038/labinvest.2011.130   (Journal Full-text)

The mitochondrial protein frataxin (FXN) is known to be involved in mitochondrial iron homeostasis and iron-sulfur cluster biogenesis. It is discussed to modulate function of the electron transport chain and production of reactive oxygen species (ROS). FXN loss in neurons and heart muscle cells causes an autosomal-dominant mitochondrial disorder, Friedreich's ataxia. Recently, tumor induction after targeted FXN deletion in liver and reversal of the tumorigenic phenotype of colonic carcinoma cells following FXN overexpression were described in the literature, suggesting a tumor suppressor function. We hypothesized that a partial reversal of the malignant phenotype of glioma cells should occur after FXN transfection, if the mitochondrial protein has tumor suppressor functions in these brain tumors. In astrocytic brain tumors and tumor cell lines, we observed reduced FXN levels compared with non-neoplastic astrocytes. Mitochondrial content (citrate synthase activity) was not significantly altered in U87MG glioblastoma cells stably overexpressing FXN (U87-FXN). Surprisingly, U87-FXN cells exhibited increased cytoplasmic ROS levels, although mitochondrial ROS release was attenuated by FXN, as expected. Higher cytoplasmic ROS levels corresponded to reduced activities of glutathione peroxidase and catalase, and lower glutathione content. The defect of antioxidative capacity resulted in increased susceptibility of U87-FXN cells against oxidative stress induced by H(2)O(2) or buthionine sulfoximine. These characteristics may explain a higher sensitivity toward staurosporine and alkylating drugs, at least in part. On the other hand, U87-FXN cells exhibited enhanced growth rates in vitro under growth factor-restricted and hypoxic conditions and in vivo using tumor xenografts in nude mice. These data contrast to a general tumor suppressor function of FXN but suggest a dual, pro-proliferative but chemosensitizing role in astrocytic tumors.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
glioblastoma  IMP 401793715 RGD 
glioblastoma  ISOFXN (Homo sapiens)401793715; 401793715 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to glucose starvation  IEP 401793715 RGD 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
mitochondrion  IDA 401793715MMO:0000662RGD 

Objects Annotated

Genes (Rattus norvegicus)
Fxn  (frataxin)

Genes (Mus musculus)
Fxn  (frataxin)

Genes (Homo sapiens)
FXN  (frataxin)


Additional Information