The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/8/411/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 3, August 2, 1999 411-422

Original Article

Regulation of Apoptosis in Myeloid Cells by Interferon Consensus Sequence–Binding Protein

Lucia Gabrielea, Jan Phunga, Jon Fukumotoa, David Segala, I-Ming Wangb, Paraskevi Giannakakouc, Nathalie A. Giesea, Keiko Ozatob, and Herbert C. Morse, IIIa

a From The Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases
b The Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development
c The Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-0760
LIP, NIAID, Bldg. 7, Rm. 308, 7 Center Dr., MSC 0760, NIH, Bethesda, MD 20892-0760.301-402-0077301-435-6525

lgabriele{at}atlas.niaid.nih.gov

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-XL. These data suggest that ICSBP modulates survival of myeloid cells by regulating expression of apoptosis-related genes.

Key Words: apoptosis • caspase • chronic myelogenous leukemia • interferon • interferon consensus sequence–binding protein

1used in this paper: CHX, cycloheximide; CML, chronic myelogenous leukemia; FMK, fluoromethyl ketone; ICSBP, interferon consensus sequence–binding protein; IRF, interferon regulatory factor; ISGF, IFN-stimulated gene factor; ISRE, interferon-stimulated response element; RT, reverse transcriptase; STAT, signal transducer and activator of transcription; TUNEL, TdT-mediated dUTP-biotin nick-end labeling

© 1999 The Rockefeller University Press


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