Abstract
Strong stimulation of the T-cell receptor (TCR) on cycling peripheral T cells causes their apoptosis by a process called TCR-activation-induced cell death (TCR-AICD). TCR-AICD occurs from a late G1 phase cell-cycle check point independently of the 'tumour suppressor' protein p53. Disruption of the gene for the E2F-1 transcription factor, an inducer of apoptosis, causes significant increases in T-cell number and splenomegaly. Here we show that T cells undergoing TCR-AICD induce the p53-related gene p73, another mediator of apoptosis, which is hypermethylated in lymphomas. Introducing a dominant-negative E2F-1 protein or a dominant-negative p73 protein into T cells protects them from TCR-mediated apoptosis, whereas dominant-negative E2F-2, E2F-4 or p53 does not. Furthermore, E2F-1-null or p73-null primary T cells do not undergo TCR-mediated apoptosis either. We conclude that TCR-AICD occurs from a late G1 cell-cycle checkpoint that is dependent on both E2F-1 and p73 activities. These observations indicate that, unlike p53, p73 serves to integrate receptor-mediated apoptotic stimuli.
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*
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Carrier Proteins*
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Cell Cycle Proteins*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2F2 Transcription Factor
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E2F4 Transcription Factor
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G1 Phase
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Gene Products, tat / genetics
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Gene Products, tat / metabolism
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Genes, Tumor Suppressor
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Humans
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In Situ Nick-End Labeling
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Jurkat Cells
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Metabolism
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Mice
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology*
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Receptors, Antigen, T-Cell / physiology*
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Recombinant Fusion Proteins
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Retinoblastoma-Binding Protein 1
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T-Lymphocytes / metabolism
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T-Lymphocytes / physiology*
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Transcription Factor DP1
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Tumor Protein p73
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Tumor Suppressor Proteins
Substances
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Arid4a protein, mouse
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Carrier Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2F1 protein, human
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E2F2 Transcription Factor
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E2F2 protein, human
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E2F4 Transcription Factor
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E2F4 protein, human
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E2f1 protein, mouse
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E2f4 protein, mouse
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Gene Products, tat
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Nuclear Proteins
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Receptors, Antigen, T-Cell
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Recombinant Fusion Proteins
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Retinoblastoma-Binding Protein 1
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TP73 protein, human
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Transcription Factor DP1
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Transcription Factors
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Trp73 protein, mouse
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Tumor Protein p73
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Tumor Suppressor Proteins