Ivanov V N, Nikolić-Zugić J
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
J Biol Chem. 1997 Mar 28;272(13):8558-66.
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.
许多导致细胞凋亡性死亡的信号是通过诱导其他（可能是死亡效应器）介质的转录和翻译来发挥作用的，并且众所周知，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，细胞凋亡的转录调控尚未完全被理解。为了深入了解T细胞发育过程中与信号诱导的细胞凋亡相关的核事件，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。利用T细胞受体（TCR）信号通路或其部分（αCD3/TCR单克隆抗体、Ca2+离子载体或蛋白激酶C激活佛波酯）的刺激，或拮抗T细胞杂交瘤中TCR信号和细胞凋亡的刺激（福斯高林，一种环磷酸腺苷信号激活剂），都会导致DP胸腺细胞大量凋亡。与此同时，这些刺激诱导了诱导型转录因子（TFs）NF-κB/RelA-p50、AP-1（Fos-Jun）和NUR-77在质量上相似但数量上独特的模式。我们将注意力集中在AP-1（Fos-Jun）复合物的作用上，该复合物被上述所有刺激强烈诱导，因此是促凋亡TF的候选者。然而，我们发现，从Fos-/-小鼠中DP细胞自发和诱导死亡增加的情况判断，AP-1/c-Fos的诱导对于延长DP胸腺细胞寿命至关重要。直接支持这一假设的是，反义寡核苷酸实验表明，c-Fos在保护正常DP胸腺细胞免受Ca2+和cAMP诱导的细胞凋亡方面起着至关重要的作用，但对TCR介导的死亡不起作用。总之，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。
