A common E2F-1 and p73 pathway mediates cell death induced by TCR activation
A common E2F-1 and p73 pathway mediates cell death induced by TCR activation
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DOI：
10.1038/35036608
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发表时间：
2000-10-05
期刊：
影响因子：
64.8
通讯作者：
Dowdy, SF
中科院分区：
文献类型：
--
作者：
Lissy, NA;Davis, PK;Dowdy, SF
循环外周T细胞上的T细胞受体（TCR）的强刺激通过称为TCR活化诱导的细胞死亡（TCR-AICD）的过程引起其凋亡（1-3）。TCR-AICD发生于G1期晚期细胞周期检查点（4），与“肿瘤抑制”蛋白p53无关（参考文献5，6）。E2 F-1转录因子基因（7，8）（细胞凋亡诱导剂（9-11））的破坏导致T细胞数量显著增加和脾肿大（12-15）。在这里，我们表明经历TCR-AICD的T细胞诱导p53相关基因p73，另一种凋亡介导物（16），其在淋巴瘤中高甲基化（17，18）。将显性负性E2 F-1蛋白或显性负性p73蛋白引入T细胞可保护它们免受TCR介导的凋亡，而显性负性E2 F-2、E2 F-4或p53则不能。此外，E2 F-1-null或p73-null原代T细胞也不经历TCR介导的凋亡。我们的结论是，TCR-AICD发生在G1期细胞周期检查点，这是依赖于E2 F-1和p73的活动。这些观察结果表明，与p53不同，p73用于整合受体介导的凋亡刺激。
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)(1-3). TCR-AICD occurs from a late G1 phase cell-cycle check point(4) independently of the 'tumour suppressor' protein p53 (refs 5, 6). Disruption of the gene for the E2F-1 transcription factor(7,8), an inducer of apoptosis(9-11), causes significant increases in T-cell number and splenomegaly(12-15). Here we show that T cells undergoing TCR-AICD induce the p53-related gene p73, another mediator of apoptosis(16), which is hypermethylated in lymphomas(17,18). 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.