Functional correction of FA-C cells with FANCC suppresses the expression of interferon gamma-inducible genes.
Because hematopoietic cells derived from Fanconi anemia (FA) patients of the C-complementation group (FA-C) are hypersensitive to the inhibitory effects of interferon gamma (IFNgamma), the products of certain IFNgamma-inducible genes known to influence hematopoietic cell survival were quantified. High constitutive expression of the IFNgamma-inducible genes, IFN-stimulated gene factor 3 gamma subunit (ISGF3gamma), IFN regulatory factor-1 (IRF-1), and the cyclin-dependent kinase inhibitor p21(WAF1) was found in FANCC mutant B lymphoblasts, low-density bone marrow cells, and murine embryonic fibroblasts. Paradoxically, these cells do not activate signal transducer and activator of transcription (STAT) 1 properly. In an attempt to clarify mechanisms by which FA-C cells overexpress IFNgamma-inducible genes in the face of defective STAT1 phosphorylation, it was reasoned that decreased levels of activated STAT1 might result in reduced expression of a hematopoietic IFNgamma-responsive protein that normally modulates expression of other IFNgamma-responsive genes. Levels of the IFNgamma-inducible factor IFN consensus sequence binding protein (ICSBP), a negative trans-acting regulator of some IFNgamma-inducible genes, were quantified. ICSBP levels were reduced in FA-C B lymphoblasts and MEFs. However, enforced expression of ICSBP failed to down-regulate IRF-1, ISGF3gamma, and p21(WAF1). Thus, the FANCC protein functions to modulate expression of a family of genes that in normal cells are inducible only by specific environmental cues for apoptosis or mitogenic inhibition, but it does so independently of the classic IFN-STAT1 pathway and is not the direct result of reduced ICSBP expression.
Fagerlie
S R
SR
Division of Hematology and Medical Oncology, the Department of Molecular and Medical Genetics, and the Oregon Cancer Center, Oregon Health Sciences University, Portland, OR, USA.
Diaz
J
J
Christianson
T A
TA
McCartan
K
K
Keeble
W
W
Faulkner
G R
GR
Bagby
G C
GC
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005199:Fanconi Anemia / Q000235:genetics* / Q000473:pathology; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D005347:Fibroblasts / Q000737:chemistry; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000473:pathology; D004854:Herpesvirus 4, Human; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000235:genetics; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000032:analysis; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D000099185:Interferon Regulatory Factor-8
D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D007371:Interferon-gamma; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C497651:FANCC protein, human; C497652:Fancc protein, mouse; C494257:IRF1 protein, human; C494227:IRF9 protein, human; C494258:Irf1 protein, mouse; C494228:Isgf3g protein, mouse; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse