Abstract
Inflammation influences the development of cancer. The nitric oxide synthase (NOS2) is induced by inflammatory cytokines, e.g., tumor necrosis factor alpha and interleukin 1beta, and produces nitric oxide (NO*), a critical mediator of the inflammatory response. Because p53 governs NO* production by transcriptionally transrepressing NOS2, we used a genetic strategy to determine whether NO* and p53 cooperatively regulate tumorigenesis. Lymphomas developed more rapidly in p53-/-NOS2-/- or p53-/-NOS2+/- mice than in p53-/-NOS2+/+ mice that were cross-bred into a >95% C57BL6 background and maintained in a pathogen-free condition. Likewise, sarcomas and lymphomas developed faster in p53+/-NOS2-/- or p53+/-NOS2+/- than in p53+/-NOS2+/+ mice. When compared with the double knockout mice, p53-/-NOS2+/+ mice showed a higher apoptotic index and a decreased proliferation index with an increased expression of death receptor ligands, CD95-L and tumor necrosis factor-related apoptosis-inducing ligand, and the cell cycle checkpoint protein, p21(waf1), in the spleen and thymus before tumor development. Furthermore, mice deficient in both p53 and NOS2 produced a high level of anti-inflammatory interleukin 10 when compared with p53-deficient mice. These studies provide genetic and mechanistic evidence that NO* can suppress tumorigenesis.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / physiology
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Apoptosis Regulatory Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / biosynthesis
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Disease Models, Animal
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Fas Ligand Protein
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Female
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Inbreeding
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Inflammation Mediators / metabolism*
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Interleukin-10 / biosynthesis
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Ki-67 Antigen / biosynthesis
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Lymphoma, T-Cell / enzymology
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Lymphoma, T-Cell / metabolism*
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Lymphoma, T-Cell / pathology
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Male
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Membrane Glycoproteins / biosynthesis
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nitric Oxide / metabolism*
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Nitric Oxide Synthase / deficiency
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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Sarcoma, Experimental / enzymology
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Sarcoma, Experimental / metabolism*
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Sarcoma, Experimental / pathology
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / genetics
Substances
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Apoptosis Regulatory Proteins
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Fas Ligand Protein
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Fasl protein, mouse
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Inflammation Mediators
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Ki-67 Antigen
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Membrane Glycoproteins
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TNF-Related Apoptosis-Inducing Ligand
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Protein p53
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Interleukin-10
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Nitric Oxide
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse