A common E2F-1 and p73 pathway mediates cell death induced by TCR activation.
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.
Lissy
N A
NA
Howard Hughes Medical Institute, Department of Pathology, Washington University School of Medicine, St Louis Missouri 63110, USA.
Davis
P K
PK
Irwin
M
M
Kaelin
W G
WG
Dowdy
S F
SF
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050704:E2F4 Transcription Factor; D016193:G1 Phase; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D020287:In Situ Nick-End Labeling; D019169:Jurkat Cells; D008660:Metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D056465:Retinoblastoma-Binding Protein 1; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; C493754:E2f1 protein, mouse; C493763:E2f4 protein, mouse; D015696:Gene Products, tat; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D056465:Retinoblastoma-Binding Protein 1; C000606460:TP73 protein, human; D050680:Transcription Factor DP1; D014157:Transcription Factors; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins