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PMID: 10430629 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein.

The Journal of experimental medicine ·Vol. 190 ·No. 3 ·1999-08-02 ·Pages 411-21

Gabriele L, Phung J, Fukumoto J, Segal D, Wang IM, Giannakakou P, Giese NA, Ozato K, Morse HC

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.

MeSH Terms
Amino Acid Chloromethyl Ketones/pharmacology Animals Apoptosis/genetics,immunology Bone Marrow Cells Caspases/biosynthesis,genetics,metabolism Cells, Cultured Consensus Sequence/immunology Cysteine Proteinase Inhibitors/pharmacology Etoposide/antagonists & inhibitors,pharmacology Gene Expression Regulation/drug effects,immunology Hematopoietic Stem Cells/enzymology,immunology,metabolism,pathology Humans Interferon Regulatory Factors Interferons/pharmacology Lymph Nodes Mice Mice, Knockout Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors,biosynthesis Recombinant Proteins/biosynthesis,genetics Repressor Proteins/biosynthesis,genetics,physiology Spleen U937 Cells bcl-X Protein
Chemicals
Amino Acid Chloromethyl Ketones BCL2L1 protein, human Bcl2l1 protein, mouse Cysteine Proteinase Inhibitors Interferon Regulatory Factors Proto-Oncogene Proteins c-bcl-2 Recombinant Proteins Repressor Proteins bcl-X Protein benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone interferon regulatory factor-8 Etoposide Interferons Caspases
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Gabriele L
Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-0760, USA. [email protected]
Phung J
Fukumoto J
Segal D
Wang I M
Giannakakou P
Giese N A
Ozato K
Morse H C
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.190.3.411
Email
[email protected]
Published
1999-08-02
Pages
411-21
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2195590
Subset
IM
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1084/jem.190.3.411 PMC Full Text View journal details
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