Abstract
Mice with a null mutation of the gene encoding interferon consensus sequence-binding protein (ICSBP) develop a disease with marked expansion of granulocytes and macrophages that frequently progresses to a fatal blast crisis, thus resembling human chronic myelogenous leukemia (CML). One important feature of CML is decreased responsiveness of myeloid cells to apoptotic stimuli. Here we show that myeloid cells from mice deficient in ICSBP exhibit reduced spontaneous apoptosis and a significant decrease in sensitivity to apoptosis induced by DNA damage. In contrast, apoptosis in thymocytes from ICSBP-deficient mice is unaffected. We also show that overexpression of ICSBP in the human U937 monocytic cell line enhances the rate of spontaneous apoptosis and the sensitivity to apoptosis induced by etoposide, lipopolysaccharide plus ATP, or rapamycin. Programmed cell death induced by etoposide was specifically blocked by peptides inhibitory for the caspase-1 or caspase-3 subfamilies of caspases. Studies of proapoptotic genes showed that cells overexpressing ICSBP have enhanced expression of caspase-3 precursor protein. In addition, analyses of antiapoptotic genes showed that overexpression of ICSBP results in decreased expression of Bcl-X(L). These data suggest that ICSBP modulates survival of myeloid cells by regulating expression of apoptosis-related genes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Apoptosis / genetics
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Apoptosis / immunology*
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Bone Marrow Cells
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Caspases / biosynthesis
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Caspases / genetics
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Caspases / metabolism
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Cells, Cultured
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Consensus Sequence / immunology*
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Cysteine Proteinase Inhibitors / pharmacology
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Etoposide / antagonists & inhibitors
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Etoposide / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / immunology
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Hematopoietic Stem Cells / enzymology
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Hematopoietic Stem Cells / immunology
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Hematopoietic Stem Cells / metabolism
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Hematopoietic Stem Cells / pathology*
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Humans
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Interferon Regulatory Factors
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Interferons / pharmacology*
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Lymph Nodes
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Mice
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Mice, Knockout
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / genetics
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Repressor Proteins / biosynthesis
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Repressor Proteins / genetics
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Repressor Proteins / physiology*
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Spleen
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U937 Cells
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bcl-X Protein
Substances
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Amino Acid Chloromethyl Ketones
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BCL2L1 protein, human
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Bcl2l1 protein, mouse
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Cysteine Proteinase Inhibitors
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Interferon Regulatory Factors
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Proteins
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Repressor Proteins
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bcl-X Protein
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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interferon regulatory factor-8
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Etoposide
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Interferons
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Caspases