Activation of the nuclear factor κB pathway by astrocyte elevated gene-1:: Implications for tumor progression and metastasis
Activation of the nuclear factor κB pathway by astrocyte elevated gene-1:: Implications for tumor progression and metastasis
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DOI：
10.1158/0008-5472.can-05-3029
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发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Fisher, PB
中科院分区：
文献类型：
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作者：
Emdad, L;Sarkar, D;Fisher, PB
星形胶质细胞升高基因1 （AEG-1）最初通过快速减法杂交方法在原代人胎儿星形胶质细胞中被鉴定为HIV-1和肿瘤坏死因子α (tnf - α)诱导的转录物。有趣的是，在乳腺癌、多形性胶质母细胞瘤和黑色素瘤细胞亚群中，AEG-1的表达升高，并且AEG-1与Ha-ras协同促进永生化黑色素细胞的转化。转录因子核因子κ B （nf - κ B）是一种tnf - α下游信号成分，其激活与包括癌症在内的几种人类疾病有关，nf - κ B控制着参与肿瘤进展和转移的多种基因的表达。我们现在证明了AEG-1是NF-kappa B的一个重要的正调节因子，通过复制不能力腺病毒（Ad.AEG-1）在HeLa细胞中增强AEG-1的表达，显著增加NF-kappa B转录激活因子p50/p65复合物的结合，AEG-1诱导NF-kappa B活化与I kappa B α的降解和p65的核易位相对应，导致NF-kappa B下游基因的诱导。表达mt32I κ B α超抑制因子（Ad）的腺病毒感染。抑制p65核易位的I kappa B α -mt32)抑制了aeg -1诱导的琼脂克隆效率的提高和HeLa细胞基质侵袭的增加。我们还发现，tnf - α处理导致AEG-1和p65的核易位，其中这两种蛋白物理相互作用，表明AEG-1激活NF-kappa B的潜在机制。我们的研究结果表明，AEG-1激活NF-kappa B可能代表了AEG-1促进锚定非依赖性生长和侵袭的关键分子机制，这是肿瘤表型的两个中心特征。
Astrocyte elevated gene-1 (AEG-1) was initially identified as an HIV-1- and tumor necrosis factor alpha (TNF-alpha)-inducible transcript in primary human fetal astrocytes by a rapid subtraction hybridization approach. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells and AEG-1 cooperates with Ha-ras to promote transformation of immortalized melanocytes. Activation of the transcription factor nuclear factor kappa B (NF-kappa B), a TNF-alpha downstream signaling component, is associated with several human illnesses, including cancer, and NF-kappa B controls the expression of multiple genes involved in tumor progression and metastasis. We now document that AEG-1 is a significant positive regulator of NF-kappa B. Enhanced expression of AEG-1 via a replication-incompetent adenovirus (Ad.AEG-1) in HeLa cells markedly increased binding of the transcriptional activator p50/p65 complex of NF-kappa B. The NF-kappa B activation induced by AEG-1 corresponded with degradation Of I kappa B alpha and nuclear translocation of p65 that resulted in the induction of NF-kappa B downstream genes. Infection with an adenovirus expressing the mt32I kappa B alpha superrepressor (Ad.I kappa B alpha-mt32), which prevents p65 nuclear translocation, inhibited AEG-1-induced enhanced agar cloning efficiency and increased matrigel invasion of HeLa cells. We also document that TNF-alpha treatment resulted in nuclear translocation of both AEG-1 and p65 wherein these two proteins physically interacted, suggesting a potential mechanism by which AEG-1 could activate NF-kappa B. Our findings suggest that activation of NF-kappa B by AEG-1 could represent a key molecular mechanism by which AEG-1 promotes anchorage-independent growth and invasion, two central features of the neoplastic phenotype.