title: Inactivation of the Fanconi anemia group C gene augments interferon-gamma-induced apoptotic responses in hematopoietic cells.
abstract: Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus (FAC -/-) are hypersensitive to the mitotic inhibitory effects of interferon (IFN-gamma). We tested the hypothesis that HPC from the bone marrow of Fanconi group C children are similarly hypersensitive and that the fas pathway is involved in affecting programmed cell death in response to low doses of IFN-gamma. In normal human and murine HPC, IFN-gamma primed the fas pathway and induced both fas and interferon response factor-1 (IRF-1) gene expression. These IFN-gamma-induced apoptotic responses in HPC from the marrow of a child with FA of the C group (FA-C) and in FAC -/- mice occurred at significantly lower IFN doses (by an order of magnitude) than did the apoptotic responses of normal HPC. Treatment of FA-C CD34+ cells with low doses of recombinant IFN-gamma, inhibited growth of colony forming unit granulocyte-macrophage and burst-forming unit erythroid, while treatment with blocking antibodies to fas augmented clonal growth and abrogated the clonal inhibitory effect of IFN-gamma. Transfer of the normal FAC gene into FA-C B-cell lines prevented mitomycin C-induced apoptosis, but did not suppress fas expression or inhibit the primed fas pathway. However, the kinetics of Stat1-phosphate decay in IFN-gamma-treated cells was prolonged in mutant cells and was normalized by transduction of the normal FAC gene. Therefore, the normal FAC protein serves, in part, to modulate IFN-gamma signals. HPC bearing inactivating mutations of FAC fail to normally modulate IFN-gamma signals and, as a result, undergo apoptosis executed through the fas pathway.
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland 97201-3098, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Rathbun
authors.forename: G R
authors.initials: GR
authors.lastname: Faulkner
authors.forename: M H
authors.initials: MH
authors.lastname: Ostroski
authors.forename: T A
authors.initials: TA
authors.lastname: Christianson
authors.forename: G
authors.initials: G
authors.lastname: Hughes
authors.forename: G
authors.initials: G
authors.lastname: Jones
authors.forename: R
authors.initials: R
authors.lastname: Cahn
authors.forename: R
authors.initials: R
authors.lastname: Maziarz
authors.forename: G
authors.initials: G
authors.lastname: Royle
authors.forename: W
authors.initials: W
authors.lastname: Keeble
authors.forename: M C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: M
authors.initials: M
authors.lastname: Grompe
authors.forename: P A
authors.initials: PA
authors.lastname: Tower
authors.forename: G C
authors.initials: GC
authors.lastname: Bagby
mesh_terms: D000741:Anemia, Aplastic / Q000209:etiology / Q000503:physiopathology; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D005199:Fanconi Anemia / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D053222:Fas Ligand Protein; D005816:Genetic Complementation Test; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016685:Mitomycin / Q000494:pharmacology; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins; D015398:Signal Transduction; D014162:Transfection; D019014:fas Receptor / Q000235:genetics / Q000502:physiology
chemical_list: D017304:Annexin A5; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; C505661:FASLG protein, human; C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D011994:Recombinant Proteins; D019014:fas Receptor; D016685:Mitomycin; D007371:Interferon-gamma