Aurora-A regulation of nuclear factor-κB signaling by phosphorylation of IκBα
Aurora-A regulation of nuclear factor-κB signaling by phosphorylation of IκBα
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DOI：
10.1158/0008-5472.can-06-2272
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发表时间：
2007-02-15
期刊：
影响因子：
11.2
通讯作者：
Linardopoulos, Spiros
中科院分区：
文献类型：
--
作者：
Briassouli, Paraskevi;Chan, Florence;Linardopoulos, Spiros
Aurora-A/STK15 基因编码一种在癌症中经常被扩增的激酶。 Aurora-A 在哺乳动物细胞中的过度表达会导致中心体扩增、遗传不稳定和转化。在这项研究中，我们发现 Aurora-A 通过 I kappa B α 磷酸化激活核因子 kappa B (NF-kappa B)。抑制内源性 Aurora-A 可减少肿瘤坏死因子 α (TNF α) 诱导的 I kappa B α 降解。我们分析了原发性人类乳腺癌，13.6% 的样本显示 Aurora-A 基因扩增，所有这些样本均表现出 NF-kappa B 的核定位。我们认为，这一亚组乳腺癌患者可能受益于抑制 Aurora-A。我们还表明，通过 Aurora-A 耗竭下调 NF-kappa B 可以增强顺铂依赖性细胞凋亡。这些数据定义了 Aurora-A 在调节 I kappa B α 中的新作用，这对于激活 NF-kappa B 导向的基因表达至关重要，并且当该基因在人类肿瘤中扩增和过度表达时，可能是 Aurora-A 致癌作用的部分原因。
The Aurora-A/STK15 gene encodes a kinase that is frequently amplified in cancer. Overexpression of Aurora-A in mammalian cells leads to centrosome amplification, genetic instability, and transformation. In this study, we show that Aurora-A activates nuclear factor-kappa B (NF-kappa B) via I kappa B alpha phosphorylation. Inhibition of endogenous Aurora-A reduces tumor necrosis factor alpha (TNF alpha)-induced I kappa B alpha degradation. We analyzed primary human breast cancers, and 13.6% of samples showed Aurora-A gene amplification, all of which exhibited nuclear localization of NF-kappa B. We propose that this subgroup of patients with breast cancer might benefit from inhibiting Aurora-A. We also show that down-regulation of NF-kappa B via Aurora-A depletion can enhance cisplatin-dependent apoptosis. These data define a new role for Aurora-A in regulating I kappa B alpha that is critical for the activation of NF-kappa B-directed gene expression and may be partially responsible for the oncogenic effect of Aurora-A when the gene is amplified and overexpressed in human tumors.