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Cited by 114Cell death mechanisms and regulationCancer-related Molecular PathwaysAcute Myeloid Leukemia Research

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

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Gabriele, Lucia, Phung, Jan, Fukumoto, Jon, Segal, David, Wang, I-Ming, Giannakakou, Paraskevi, Giese, Nathalie A., Ozato, Keiko, Morse, Herbert C.·1999·The Journal of Experimental Medicine
DOI 10.1084/jem.190.3.411PMC PMC2195590
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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-XL. These data suggest that ICSBP modulates survival of myeloid cells by regulating expression of apoptosis-related genes.

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Crossref · 10.1084/jem.190.3.411

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Figures

Figure 1 Spontaneous proliferation and apoptosis in cells of ICSBP−/− mice. (A) Cells were cultured for 24–72 h and pulsed with [3H]thymidine for the last 18 h of culture. (B) Cells from −/− mice and +/+ littermates were cultured for 1 and 2 d and analyzed for apoptosis by TUNEL assay. Data are representative of three experiments using 10–16-wk-old mice.
Figure 1 Spontaneous proliferation and apoptosis in cells of ICSBP−/− mice. (A) Cells were cultured for 24–72 h and pulsed with [3H]thymidine for the last 18 h of culture. (B) Cells from −/− mice and +/+ littermates were cultured for 1 and 2 d and analyzed for apoptosis by TUNEL assay. Data are representative of three experiments using 10–16-wk-old mice.CC BY-NC-SA · PubMed Central
Figure 2 Macrophages and granulocytes account for reduced levels of apoptosis in spleen and bone marrow cells of ICSBP−/− mice. Cells from ICSBP−/− mice and ICSBP+/+ littermates were cultured for 18 h alone, with etoposide (10 μg/ml), or with TNF-α (30 ng/ml) plus CHX (10 μg/ml), stained with the indicated Ab, and fixed for TUNEL assays. Data are representative of three experiments using 10–16-wk-old mice.
Figure 2 Macrophages and granulocytes account for reduced levels of apoptosis in spleen and bone marrow cells of ICSBP−/− mice. Cells from ICSBP−/− mice and ICSBP+/+ littermates were cultured for 18 h alone, with etoposide (10 μg/ml), or with TNF-α (30 ng/ml) plus CHX (10 μg/ml), stained with the indicated Ab, and fixed for TUNEL assays. Data are representative of three experiments using 10–16-wk-old mice.CC BY-NC-SA · PubMed Central
Figure 3 U937 cells overexpressing ICSBP show increased spontaneous apoptosis. U937+ and U937− cells were cultured for the indicated times and assayed for apoptosis by TUNEL. Data are representative of three independent experiments.
Figure 3 U937 cells overexpressing ICSBP show increased spontaneous apoptosis. U937+ and U937− cells were cultured for the indicated times and assayed for apoptosis by TUNEL. Data are representative of three independent experiments.CC BY-NC-SA · PubMed Central
Figure 4 Apoptosis induced by etoposide or LPS plus ATP is enhanced in U937 cells overexpressing ICSBP. Cells were treated with reagents as indicated in Materials and Methods and assayed for apoptosis by TUNEL. Data are representative of three or more experiments. Solid bars, untreated cells; hatched bars, treated cells.
Figure 4 Apoptosis induced by etoposide or LPS plus ATP is enhanced in U937 cells overexpressing ICSBP. Cells were treated with reagents as indicated in Materials and Methods and assayed for apoptosis by TUNEL. Data are representative of three or more experiments. Solid bars, untreated cells; hatched bars, treated cells.CC BY-NC-SA · PubMed Central
Figure 5 Caspase inhibitors block apoptosis in cells overexpressing ICSBP. Cells were incubated with caspase inhibitors ZVAD-FMK and BD-FMK and the inactive reagent ZFA-FMK for 1 h before addition of etoposide. TUNEL assays were performed 16 h later. Data are representative of three experiments.
Figure 5 Caspase inhibitors block apoptosis in cells overexpressing ICSBP. Cells were incubated with caspase inhibitors ZVAD-FMK and BD-FMK and the inactive reagent ZFA-FMK for 1 h before addition of etoposide. TUNEL assays were performed 16 h later. Data are representative of three experiments.CC BY-NC-SA · PubMed Central
Figure 6 Caspase expression is modulated in cells overexpressing ICSBP. U937− and U937+ cells were treated to induce apoptosis with the indicated reagents. Left, RT-PCR analyses of transcripts for the indicated genes. Right, Western blot analysis of caspase expression. Data are representative of three experiments.
Figure 6 Caspase expression is modulated in cells overexpressing ICSBP. U937− and U937+ cells were treated to induce apoptosis with the indicated reagents. Left, RT-PCR analyses of transcripts for the indicated genes. Right, Western blot analysis of caspase expression. Data are representative of three experiments.CC BY-NC-SA · PubMed Central
Figure 7 Regulation of Bcl-XL expression. (A) RT-PCR analyses of Bcl-XL transcripts in untreated cells and cells treated for 18 h with TNF-α plus CHX or with etoposide. (B) Western blot analyses of Bcl-XL levels in U937− cells stimulated for the indicated times with IFN-α or IFN-γ. (C) Luciferase assays of Bcl-XL promoter activity in RAW cells. Cells were transfected with vector either alone or with IRF-1, IRF-2, or ICSBP. Data are representative of two experiments.
Figure 7 Regulation of Bcl-XL expression. (A) RT-PCR analyses of Bcl-XL transcripts in untreated cells and cells treated for 18 h with TNF-α plus CHX or with etoposide. (B) Western blot analyses of Bcl-XL levels in U937− cells stimulated for the indicated times with IFN-α or IFN-γ. (C) Luciferase assays of Bcl-XL promoter activity in RAW cells. Cells were transfected with vector either alone or with IRF-1, IRF-2, or ICSBP. Data are representative of two experiments.CC BY-NC-SA · PubMed Central
Figure 8 Western blot analyses of p53 expression in U937− and U937+ cells.
Figure 8 Western blot analyses of p53 expression in U937− and U937+ cells.CC BY-NC-SA · PubMed Central

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  1. Sambrook, 1989, Molecular Cloning

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Metadata

Authors
Gabriele, L., Phung, J., Fukumoto, J., Segal, D., Wang, I.-M., Giannakakou, P., Giese, N. A., Ozato, K., & Morse, H. C.
Affiliations
  • National Institute of Allergy and Infectious Diseases (US)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
  • National Institutes of Health (US)
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
1999-08-02
Volume
190
Issue
3
Pages
411-422
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.190.3.411
PMC
PMC2195590
OpenAlex
W2115970169
Cited by
114
References
74
Citations by year
2026: 1 · 2025: 2 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 1 · 2018: 2 · 2017: 2 · 2016: 2 · 2015: 6 · 2014: 6 · 2013: 7 · 2012: 5
FWCI
2.42
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords
IRF8, apoptosis, myeloid cells, chronic myeloid leukemia, spontaneous apoptosis, DNA damage-induced apoptosis, caspase-3, caspase-1, Bcl-xL, anti-apoptotic genes, pro-apoptotic genes, etoposide, rapamycin, lipopolysaccharide, monocytic cells, cell survival
MeSH terms
Interferon Regulatory Factor-8, Amino Acid Chloromethyl Ketones, Animals, Bone Marrow Cells, Cells, Cultured, Etoposide, Gene Expression Regulation, Hematopoietic Stem Cells, Humans, Interferons, Lymph Nodes, Recombinant Proteins, Repressor Proteins, Spleen, Cysteine Proteinase Inhibitors, Consensus Sequence, Apoptosis, Mice, Knockout, Proto-Oncogene Proteins c-bcl-2, Caspases, U937 Cells, Interferon Regulatory Factors, bcl-X Protein, Mice

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