Abstract
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.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
B-Lymphocytes / metabolism
-
Bone Marrow Cells / metabolism
-
Cell Cycle Proteins*
-
Cell Line, Transformed
-
Cyclin-Dependent Kinase Inhibitor p21
-
Cyclins / genetics
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
Embryo, Mammalian
-
Fanconi Anemia / genetics*
-
Fanconi Anemia / pathology
-
Fanconi Anemia Complementation Group C Protein
-
Fanconi Anemia Complementation Group Proteins
-
Fibroblasts / chemistry
-
Gene Expression Regulation*
-
Hematopoietic Stem Cells / pathology
-
Herpesvirus 4, Human
-
Humans
-
Interferon Regulatory Factor-1
-
Interferon Regulatory Factors
-
Interferon-Stimulated Gene Factor 3
-
Interferon-Stimulated Gene Factor 3, gamma Subunit
-
Interferon-gamma / pharmacology*
-
Mice
-
Mice, Knockout
-
Mutation
-
Nuclear Proteins*
-
Phosphoproteins / genetics
-
Phosphorylation
-
Proteins / genetics*
-
Proteins / physiology
-
Regulatory Sequences, Nucleic Acid
-
Repressor Proteins / analysis
-
STAT1 Transcription Factor
-
Trans-Activators / metabolism
-
Transcription Factors / genetics
-
Transfection
Substances
-
CDKN1A protein, human
-
Cdkn1a protein, mouse
-
Cell Cycle Proteins
-
Cyclin-Dependent Kinase Inhibitor p21
-
Cyclins
-
DNA-Binding Proteins
-
FANCC protein, human
-
Fancc protein, mouse
-
Fanconi Anemia Complementation Group C Protein
-
Fanconi Anemia Complementation Group Proteins
-
IRF1 protein, human
-
IRF9 protein, human
-
Interferon Regulatory Factor-1
-
Interferon Regulatory Factors
-
Interferon-Stimulated Gene Factor 3
-
Interferon-Stimulated Gene Factor 3, gamma Subunit
-
Irf1 protein, mouse
-
Isgf3g protein, mouse
-
Nuclear Proteins
-
Phosphoproteins
-
Proteins
-
Repressor Proteins
-
STAT1 Transcription Factor
-
STAT1 protein, human
-
Stat1 protein, mouse
-
Trans-Activators
-
Transcription Factors
-
interferon regulatory factor-8
-
Interferon-gamma