Abstract
Inhibitor of Apoptosis Proteins (IAPs) are frequently overexpressed in tumors and have become promising targets for developing anti-cancer drugs. IAPs can be inhibited by natural antagonists, but a physiological requirement of mammalian IAP antagonists remains to be established. Here we show that deletion of the mouse Sept4 gene, which encodes the IAP antagonist ARTS, promotes tumor development. Sept4-null mice have increased numbers of hematopoietic stem and progenitor cells, elevated XIAP protein, increased resistance to cell death, and accelerated tumor development in an Eμ-Myc background. These phenotypes are partially suppressed by inactivation of XIAP. Our results suggest that apoptosis plays an important role as a frontline defense against cancer by restricting the number of normal stem cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Apoptosis*
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Bone Marrow Cells / cytology
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Bone Marrow Cells / metabolism
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Cell Count
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Cells, Cultured
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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Female
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Flow Cytometry
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism*
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Hematologic Neoplasms / genetics
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Hematologic Neoplasms / metabolism
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Hematologic Neoplasms / pathology
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / metabolism
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Humans
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Immunoblotting
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Kaplan-Meier Estimate
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Lymphoid Tissue / metabolism
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Lymphoid Tissue / pathology
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Lymphoma / genetics
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Lymphoma / metabolism
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Lymphoma / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Septins
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Stem Cells / cytology
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Stem Cells / metabolism*
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Suppression, Genetic
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X-Linked Inhibitor of Apoptosis Protein / genetics
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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Cytoskeletal Proteins
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X-Linked Inhibitor of Apoptosis Protein
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GTP-Binding Proteins
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Sept4 protein, mouse
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Septins