Induction of apoptosis by c-Fos protein
Induction of apoptosis by c-Fos protein
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DOI：
10.1128/mcb.16.1.211
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发表时间：
1996-01
影响因子：
5.3
通讯作者：
Gloria A. Preston;Tracy T. Lyon;Yuxin Yin;Jason E. Lang;Gregory Solomon;Lois Annab;Dayalan G. Srinivasan;David A. Alcorta;J. C. Barrett
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文献类型：
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作者：
Gloria A. Preston;Tracy T. Lyon;Yuxin Yin;Jason E. Lang;Gregory Solomon;Lois Annab;Dayalan G. Srinivasan;David A. Alcorta;J. C. Barrett
使用嵌合Fos-雌激素受体融合蛋白c-FosER，在两个叙利亚仓鼠胚胎细胞系（sup+I和sup-II）和人结肠直肠癌细胞系（RKO）中研究c-Fos在细胞凋亡中的作用。如前所述，当这两种细胞系被置于生长因子剥夺条件下时，观察到对比的反应; sup+I细胞对凋亡高度敏感，而sup-II细胞具有抗性。在这份报告中，我们表明，激活的c-FosER蛋白诱导的凋亡在sup-II癌前细胞在无血清培养基中，表明c-Fos蛋白可以诱导这些细胞的凋亡性细胞死亡。c-Fos诱导的细胞凋亡不被蛋白质合成抑制剂放线菌酮阻断，表明c-Fos转录激活活性不参与。这一结论进一步得到以下观察结果的支持：v-Fos的过表达不诱导细胞凋亡，v-Fos在转录激活方面非常熟练，但在与c-Fos相关的转录抑制活性方面存在缺陷。组成性表达Bcl-2延迟了低血清诱导的sup+I细胞凋亡的发生，并增强了sup-II细胞的存活率。此外，Bcl-2和c-FosER在sup+I或sup-II细胞中的共表达保护细胞免受c-FosER诱导的凋亡。检测了c-FosER诱导的细胞凋亡需要p53功能的可能性。大肠癌RKOp 53 +/+细胞，通常不经历无血清培养基中的凋亡，表现出凋亡的DNA片段表达和激活后的c-FosER。此外，当野生型p53蛋白在RKO细胞中通过感染乳头瘤病毒E6基因而减少时，随后的c-FosER诱导的细胞凋亡被阻断。这些数据表明，c-Fos蛋白在p53依赖性方式的细胞凋亡激活中起着因果作用。这种活性不需要新的蛋白质合成，并且被Bcl-2蛋白的过表达阻断。
The role of c-Fos in apoptosis was examined in two Syrian hamster embryo cell lines (sup+I and sup-II) and a human colorectal carcinoma cell line (RKO), using the chimeric Fos-estrogen receptor fusion protein c-FosER. As previously reported, contrasting responses were observed when these two cell lines were placed under growth factor deprivation conditions; sup+I cells were highly susceptible to apoptosis, whereas sup-II cells were resistant. In this report, we show that the activated c-FosER protein induces apoptosis in sup-II preneoplastic cells in serum-free medium, indicating that c-Fos protein can induce apoptotic cell death in these cells. c-Fos-induced apoptosis was not blocked by the protein synthesis inhibitor cycloheximide, suggesting that the c-Fos transcriptional activation activity is not involved. This conclusion was further supported by the observation that overexpression of v-Fos, which is highly proficient in transcriptional activation but deficient in the transcriptional repression activity associated with c-Fos, did not induce apoptosis. Constitutively expressed Bcl-2 delayed the onset of low-serum-induced apoptosis in sup+I cells and enhanced survival in sup-II cells. Further, coexpression of Bcl-2 and c-FosER in sup+I or sup-II cells protected the cells from c-FosER-induced apoptosis. The possibility that c-FosER-induced apoptosis requires a p53 function was examined. Colorectal carcinoma RKOp53+/+ cells, which do not normally undergo apoptosis in serum-free medium, showed apoptotic DNA fragmentation upon expression and activation of c-FosER. Further, when the wild-type p53 protein was diminished in the RKO cells by infection with the papillomavirus E6 gene, subsequent c-FosER-induced apoptosis was blocked. The data suggest that c-Fos protein plays a causal role in the activation of apoptosis in a p53-dependent manner. This activity does not require new protein synthesis and is blocked by overexpression of Bcl-2 protein.