Abstract
Leukocyte-associated Ig-like receptor-1 (LAIR-1) is a surface molecule that functions as an inhibitory receptor on natural killer cells, T lymphocytes and monocytes. Here, we provide evidence that occupancy of LAIR-1 on human myelomonocytic leukemic cell lines inhibits proliferation and leads to programmed cell death (PCD), evaluated by propidium iodide staining and transmission electron microscopy. Interestingly, PCD elicited via LAIR-1 was not blocked by different caspase inhibitors, at variance with apoptosis induced via CD95/Fas, which was prevented by the caspase-1 and caspase-8 specific inhibitors. In addition, we show that the p65 subunit of the nuclear factor kappaB (NF-kappaB), constitutively expressed in the nucleus of these cell lines, was retained in the cytoplasm upon engagement of LAIR-1. This was evident already 8 h after LAIR-1 occupancy, when apoptosis was not yet detectable by fluorometric or ultrastructural analysis. Moreover, a reduction in inhibitor kappaBalpha phosphorylation was observed after LAIR-1 engagement. As blocking of NF-kappaB activation has been shown to rescue sensitivity to anti-cancer drugs in solid tumors, we suggest that LAIR-1 may represent a possible target for pharmacological approaches aimed to potentiate anti-leukemic therapy.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Antibodies, Monoclonal / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology*
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Caspase 1 / physiology
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Caspase 3
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Caspase 8
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Caspase 9
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Caspase Inhibitors
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Caspases / physiology
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Cell Cycle / drug effects
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Cell Division / drug effects
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Cell Nucleus / metabolism
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Cysteine Proteinase Inhibitors / pharmacology
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DNA-Binding Proteins / metabolism
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Drug Design
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Fas Ligand Protein
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Gene Expression Regulation, Leukemic* / drug effects
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Humans
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I-kappa B Proteins*
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Leukemia, Myelomonocytic, Acute / genetics
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Leukemia, Myelomonocytic, Acute / metabolism
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Leukemia, Myelomonocytic, Acute / pathology*
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Membrane Glycoproteins / physiology
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism*
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / metabolism*
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Phosphorylation
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Protein Processing, Post-Translational
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Receptors, Immunologic / antagonists & inhibitors
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Receptors, Immunologic / immunology
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Receptors, Immunologic / physiology*
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Signal Transduction
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Transcription Factor RelA
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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U937 Cells / drug effects
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U937 Cells / metabolism
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fas Receptor / physiology
Substances
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Antibodies, Monoclonal
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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DNA-Binding Proteins
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FASLG protein, human
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Fas Ligand Protein
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I-kappa B Proteins
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Membrane Glycoproteins
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NF-kappa B
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NFKBIA protein, human
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Neoplasm Proteins
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Receptors, Immunologic
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Transcription Factor RelA
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fas Receptor
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leukocyte-associated immunoglobulin-like receptor 1
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NF-KappaB Inhibitor alpha
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CASP3 protein, human
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CASP8 protein, human
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CASP9 protein, human
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases
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Caspase 1