Transcription factor activation during signal-induced apoptosis of immature CD4(+)CD8(+) thymocytes. A protective role of c-Fos.
Transcription factor activation during signal-induced apoptosis of immature CD4(+)CD8(+) thymocytes. A protective role of c-Fos.
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DOI：
10.1074/jbc.272.13.8558
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发表时间：
1997-03
期刊：
影响因子：
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通讯作者：
V. Ivanov;J. Nikolić-Žugić
中科院分区：
文献类型：
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作者：
V. Ivanov;J. Nikolić-Žugić
许多导致细胞凋亡的信号是通过诱导其他(可能是死亡效应分子)介质的转录和翻译来发挥作用的，而且众所周知，刺激诱导的细胞凋亡通常可以通过抑制转录和翻译来阻断。然而，对细胞凋亡的转录调控尚不完全清楚。为了深入了解T细胞发育过程中与信号诱导凋亡相关的核事件，我们研究了体外分离的未成熟CD8(+)4(+)双阳性(DP)胸腺细胞的信号诱导凋亡。在T细胞杂交瘤中利用T细胞受体(TCR)信号通路或其部分(αCD3/TCR单抗、钙离子载体或蛋白激酶C激活佛波酯)或拮抗TCR信号和T细胞杂交瘤细胞凋亡的刺激(环状AMP信号激活剂Forsklin)可导致DP胸腺细胞大量凋亡。同时，这些刺激诱导了质上相似但数量上独特的可诱导转录因子(TF)：NF-kappaB/rela-p50、AP-1(Fos-Jun)和Nur-77。我们将注意力集中在AP-1(Fos-Jun)复合体的作用上，该复合体被上述所有刺激强烈诱导，因此是促凋亡因子的候选者。然而，我们发现AP-1/c-Fos的诱导对于延长DP胸腺细胞的寿命是至关重要的，这从增加了Fos-/-小鼠DP细胞的自发性和诱导性死亡来判断。为了直接支持这一假说，用反义寡核苷酸的实验表明，c-Fos在保护正常的DP胸腺细胞免受钙离子和cAMP诱导的凋亡而不是TCR介导的死亡方面发挥了重要作用。综上所述，这些结果证明了c-Fos在维持DP胸腺细胞寿命方面的生理作用。
Many signals that cause apoptotic cell death operate by inducing transcription and translation of other (presumably death effector) mediators, and it is well established that stimulus-induced apoptosis can often be blocked by inhibiting transcription and translation. Transcriptional regulation of apoptosis, however, is incompletely understood. To gain insight into nuclear events associated with signal-induced apoptosis during T cell development, we studied signal-induced apoptosis of ex vivo isolated immature CD8(+)4(+) double-positive (DP) thymocytes. Stimuli utilizing the T cell receptor (TCR) signaling pathway or its parts (an alphaCD3/TCR monoclonal antibody, a Ca2+ ionophore, or a protein kinase C-activating phorbol ester) or a stimulus that antagonizes TCR signaling and apoptosis in T cell hybridoma (forskolin, a cyclic AMP-signaling activator) resulted in massive apoptosis of DP thymocytes. At the same time, these stimuli induced qualitatively similar but quantitatively unique patterns of inducible transcription factors (TFs) NF-kappaB/RelA-p50, AP-1 (Fos-Jun), and NUR-77. We focused our attention on the role of AP-1 (Fos-Jun) complex, which was strongly induced by all of the above stimuli and thus was a candidate for a proapoptotic TF. However, we found that AP-1/c-Fos induction was vital in prolonging DP thymocyte life, as judged by increased spontaneous and induced death of DP cells in Fos-/- mice. In direct support of this hypothesis, experiments with antisense oligonucleotides demonstrated that c-Fos plays an essential role in protecting normal DP thymocytes from Ca2+- and cAMP-induced apoptosis but not from TCR-mediated death. Together, these results demonstrate a physiological role for c-Fos in maintaining longevity of DP thymocytes.