title: Impaired type I IFN-induced Jak/STAT signaling in FA-C cells and abnormal CD4+ Th cell subsets in Fancc-/- mice.
abstract: The Fanconi anemia (FA) group C protein, FANCC, interacts with STAT1 following stimulation with IFN-gamma and is required for proper docking of STAT1 at the IFN-gamma receptor alpha-chain (IFN-gammaRalpha, IFN-gammaR1). Consequently, loss of a functional FANCC results in decreased activation of STAT1 following IFN-gamma stimulation. Because type I IFN receptors influence the function of type II receptors, and vice versa, we conducted experiments designed to determine whether type I IFN-induced activation of other STAT proteins is compromised in FA-C cells and found that activation of STAT 1, 3, and 5 is diminished in type I IFN-stimulated cells bearing Fancc-inactivating mutations. We also determined that the reduced activation of STATs was accompanied by significant reduction of type I IFN-induced tyrosine kinase 2 and Jak1 phosphorylation. Because tyrosine kinase 2 plays a role in differentiation of Th cells, we quantified cytokine secretion from CD4+ cells and in vitro generated CD4+ Th cell subsets from splenocytes of Fancc null mice to that of heterozygous mice and discovered reduced CD4+ IFN-gamma secretion in the Fancc-/- mouse, indicating impaired Th1 differentiation. We suggest that Fancc mutations result in a subtle immunological defect owing to the failure of FANCC to normally support Jak/STAT signaling.
authors.affiliation: Oregon Health and Science University Cancer Institute, Portland, OR, USA. sfagerli@fhcrc.org
authors.forename: Sara R
authors.initials: SR
authors.lastname: Fagerlie
authors.forename: Tara
authors.initials: T
authors.lastname: Koretsky
authors.forename: Beverly
authors.initials: B
authors.lastname: Torok-Storb
authors.forename: Grover C
authors.initials: GC
authors.lastname: Bagby
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005199:Fanconi Anemia / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D020868:Gene Silencing / Q000276:immunology; D007370:Interferon Type I / Q000502:physiology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015850:Interleukin-6 / Q000502:physiology; D053613:Janus Kinase 1; D053605:Leukemia Inhibitory Factor; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D053634:TYK2 Kinase; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D007370:Interferon Type I; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D009687:Nuclear Proteins; D011506:Proteins; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse