Abstract
In this study, we demonstrate that p53 directly inhibits expression of the T cell growth factor (IL-2) in activated T cells. This repression is independent of the intrinsic transcriptional activity of p53 and is mediated by the Tax-responsive CD28RE-3'-12-O-tetradecanoylphorbol-13-acetate response element (AP1) element of the IL-2 promoter. Coexpression of the Tax oncogene causes full reversal of this repression through coordinate targeting of p300, CREB, and the NF-kappaB pathways. Paradoxically, IL-2 repression by p53 is not reversed by mdm2. Instead, mdm2 represses the IL-2 promoter by a mechanism that is synergistic with p53 and resistant to Tax reversal. The p300 structure-function studies show that these effects are linked to competitive associations among p53, Tax, and mdm2 with multiple domains of p300. The functional outcome of these antagonistic associations is revealed further by the observation that Tax and p53 induce apoptosis in activated T cells through separate and mutually exclusive pathways. Interestingly, both pathways are abrogated by mdm2. These results provide evidence that a dynamic interplay, between Tax and specific elements of the p53 network, mediates growth factor expression and programmed cell death in activated T cells.
MeSH terms
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Apoptosis / genetics
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Apoptosis / immunology
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CD28 Antigens / genetics
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism
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Dose-Response Relationship, Immunologic
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Drug Synergism
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Gene Expression Regulation / immunology*
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Genes, pX / physiology*
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Humans
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / biosynthesis*
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Interleukin-2 / genetics
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Interleukin-2 / physiology
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Jurkat Cells
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Lymphocyte Activation / genetics
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / physiology
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Promoter Regions, Genetic / immunology
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Protein Processing, Post-Translational / immunology
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-mdm2
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Response Elements / drug effects
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Response Elements / immunology
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Signal Transduction / genetics
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Signal Transduction / immunology
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Tetradecanoylphorbol Acetate / metabolism
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / physiology
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Transcription Factor AP-1 / physiology
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Transcription, Genetic / immunology
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Tumor Suppressor Protein p53 / antagonists & inhibitors
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Tumor Suppressor Protein p53 / physiology*
Substances
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CD28 Antigens
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Cyclic AMP Response Element-Binding Protein
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Interleukin-2
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NF-kappa B
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Nuclear Proteins
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Proto-Oncogene Proteins
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Trans-Activators
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Transcription Factor AP-1
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Tetradecanoylphorbol Acetate