Abstract
Published results implicate PI3 kinase as a target of oncogenic Ras activity leading to the suppression of Fas but whether other Ras targets (e.g. Raf-1) are also involved is unclear. Here we report that thymic lymphomas overexpressing Ras and Raf-1 exhibit low expression of Fas. We show that expression of Fas in these lymphomas can be increased not only in the presence of a specific inhibitor (LY294002) of P13 kinase, but also in the presence of specific inhibitor (PD98059) of MEK, downstream target of Raf-1. Both treatments result in accumulation of ERK in cytosol of lymphoma cells suggesting cross-talk between these two pathways regulating Fas expression. Treatment with PD98059 also results in apoptosis of the lymphoma cells but not of normal thymocytes expressing low Raf-1 levels. These observations provide evidence for involvement of Raf-1/MEK/ERK pathway in Ras-mediated inhibition of Fas expression and in selective promotion of survival of lymphoma cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Chromones / pharmacology
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Gene Expression Regulation, Neoplastic* / drug effects
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Lymphoma / etiology
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Lymphoma / metabolism*
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Lymphoma / pathology
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Mice
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / physiology*
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Mitogen-Activated Protein Kinases / drug effects
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Mitogen-Activated Protein Kinases / metabolism
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Morpholines / pharmacology
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Phosphoinositide-3 Kinase Inhibitors
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Signal Transduction
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Thymus Neoplasms / etiology
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Thymus Neoplasms / metabolism
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Thymus Neoplasms / pathology
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Tumor Cells, Cultured
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fas Receptor / drug effects
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fas Receptor / genetics
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fas Receptor / physiology*
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ras Proteins / genetics
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ras Proteins / physiology*
Substances
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Chromones
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Enzyme Inhibitors
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Flavonoids
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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fas Receptor
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase Kinases
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ras Proteins
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one