A common E2F-1 and p73 pathway mediates cell death induced by TCR activation

Nature. 2000 Oct 5;407(6804):642-5. doi: 10.1038/35036608.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Carrier Proteins*
  • Cell Cycle Proteins*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F2 Transcription Factor
  • E2F4 Transcription Factor
  • G1 Phase
  • Gene Products, tat / genetics
  • Gene Products, tat / metabolism
  • Genes, Tumor Suppressor
  • Humans
  • In Situ Nick-End Labeling
  • Jurkat Cells
  • Metabolism
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Receptors, Antigen, T-Cell / physiology*
  • Recombinant Fusion Proteins
  • Retinoblastoma-Binding Protein 1
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / physiology*
  • Transcription Factor DP1
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Tumor Protein p73
  • Tumor Suppressor Proteins

Substances

  • Arid4a protein, mouse
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • E2F2 Transcription Factor
  • E2F2 protein, human
  • E2F4 Transcription Factor
  • E2F4 protein, human
  • E2f1 protein, mouse
  • E2f4 protein, mouse
  • Gene Products, tat
  • Nuclear Proteins
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Proteins
  • p73 protein, human