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首页> 外文期刊>Molecular and Cellular Biology >Nuclear c-Myc plays an important role in the cytotoxicity of tumor necrosis factor alpha in tumor cells.
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Nuclear c-Myc plays an important role in the cytotoxicity of tumor necrosis factor alpha in tumor cells.

机译：核c-Myc在肿瘤坏死因子α在肿瘤细胞的细胞毒性中起重要作用。

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The phosphoprotein c-Myc has the potential to kill cells by apoptosis. To investigate whether c-Myc is involved in tumor necrosis factor alpha (TNF-alpha)-mediated cell killing, we have examined two HeLa cell lines (D98 and H21) which show dramatic differences in their susceptibilities to TNF-alpha cytotoxicity. Northern (RNA) blot analyses showed that there were no significant differences between these cell lines in basal or TNF-alpha-induced mRNA expression for a variety of proteins, including manganous superoxide dismutase, A20 zinc finger protein, plasminogen activator inhibitor type 2, and hsp70, all of which are known to influence the susceptibility of certain cells to TNF-alpha killing. On the other hand, there was a dramatic increase in c-Myc mRNA expression in TNF-alpha-sensitive D98 cells, but not in TNF-alpha-resistant H21 cells, which was only observed when the cells were treated with cycloheximide. Western blot (immunoblot) analyses revealed that even in the absence of TNF-alpha or cycloheximide, c-Myc was detectable only in nuclear extracts of TNF-alpha-sensitive D98 cells, implying a role for preexisting c-Myc in TNF-alpha killing. In support of this interpretation, a c-myc antisense oligonucleotide specifically inhibited the TNF-alpha killing of D98 cells, provided that the oligonucleotide was added 6 h prior to TNF-alpha treatment. Either dexamethasone treatment or transient expression of c-myc antisense cDNA fragments decreased nuclear c-Myc in D98 cells and rendered the cells more resistant to TNF-alpha cytotoxicity. Nuclear c-Myc was also detectable in a TNF-alpha-sensitive human HT-1080 fibrosarcoma cell line, but it was undetectable in a derivative of HT-1080 (SS-HT-1080) known to be resistant to TNF-alpha killing because of overexpression of plasminogen activator inhibitor type 2. HT-1080 cells transfected with antisense c-myc cDNA had significantly less nuclear c-Myc and were resistant to TNF-alpha cytotoxicity. Together, these data indicate that a nuclear transcription factor, c-Myc, plays an important role in sensitizing two different tumor cell types to TNF-alpha cytotoxicity.
机译：磷蛋白c-Myc具有通过凋亡杀死细胞的潜力。为了调查c-Myc是否参与肿瘤坏死因子α（TNF-alpha）介导的细胞杀伤，我们检查了两种HeLa细胞系（D98和H21），它们在对TNF-α细胞毒性的敏感性方面表现出巨大差异。 Northern（RNA）印迹分析显示，这些细胞系在多种蛋白质（包括锰超氧化物歧化酶，A20锌指蛋白，纤溶酶原激活物抑制剂2型和hsp70，已知所有这些都会影响某些细胞对TNF-α杀伤的敏感性。另一方面，在TNF-α敏感的D98细胞中c-Myc mRNA表达显着增加，而在TNF-α抵抗性H21细胞中则没有，仅当用环己酰亚胺处理细胞时才观察到。 Western印迹（免疫印迹）分析表明，即使在没有TNF-α或环己酰亚胺的情况下，c-Myc也只能在TNF-alpha敏感的D98细胞的核提取物中检测到，这暗示着c-Myc在TNF-α杀伤中的作用。为了支持这种解释，只要在TNF-α处理前6小时加入寡核苷酸，c-myc反义寡核苷酸可特异性抑制D98细胞的TNF-α杀伤。地塞米松处理或c-myc反义cDNA片段的瞬时表达均可降低D98细胞中的核c-Myc，并使细胞对TNF-α的细胞毒性更具抵抗力。在TNF-α敏感的人HT-1080纤维肉瘤细胞系中也可检测到核c-Myc，但在已知对TNF-α杀伤具有抗性的HT-1080衍生物（SS-HT-1080）中则无法检测到。反义c-myc cDNA转染的HT-1080细胞明显减少了核c-Myc的表达，并且对TNF-α细胞毒性具有抗性。总之，这些数据表明核转录因子c-Myc在使两种不同的肿瘤细胞类型对TNF-α细胞毒性敏感方面起着重要作用。

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