title: MxA overexpression reveals a common genetic link in four Fanconi anemia complementation groups.
abstract: Fanconi anemia (FA) consists of a group of at least five autosomal recessive disorders that share both clinical (e.g., birth defects and hematopoietic failure) and cellular (e.g., sensitivity to cross-linking agents and predisposition to apoptosis) features with each other. However, a common pathogenetic link among these groups has not been established. To identify genetic pathways that are altered in FA and characterize shared molecular defects, we used mRNA differential display to isolate genes that have altered expression patterns in FA cells. Here, we report that the expression of an interferon-inducible gene, MxA, is highly upregulated in cells of FA complementation groups A, B, C, and D, but it is suppressed in FA group C cells complemented with wild-type FAC cDNA as well as in non-FA cells. A posttranscriptional mechanism rather than transcriptional induction appears to account for MxA overexpression. Forced expression of MxA in Hep3B cells enhances their sensitivity to mitomycin C and induces apoptosis, similar to the FA phenotype. Thus, MxA is a downstream target of FAC and is the first genetic marker to be identified among multiple FA complementation groups. These data suggest that FA subtypes converge onto a final common pathway, which is intimately related to the interferon signaling mechanism. Constitutive activity of this pathway may explain a number of the phenotypic features of FA, particularly the pathogenesis of bone marrow failure.
authors.affiliation: Department of Medicine, Hematology-Oncology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Youssoufian
mesh_terms: D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005199:Fanconi Anemia / Q000145:classification / Q000201:enzymology / Q000235:genetics*; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D020558:GTP Phosphohydrolases / Q000096:biosynthesis / Q000235:genetics*; D019204:GTP-Binding Proteins; D015870:Gene Expression; D006041:Goats; D006367:HeLa Cells; D006801:Humans; D064547:Myxovirus Resistance Proteins; D009687:Nuclear Proteins; D010641:Phenotype; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins