CUGBP2 plays a critical role in apoptosis of breast cancer cells in response to genotoxic injury
CUGBP2 plays a critical role in apoptosis of breast cancer cells in response to genotoxic injury
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DOI：
10.1196/annals.1299.093
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发表时间：
2003-01-01
期刊：
影响因子：
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通讯作者：
Anant, S
中科院分区：
文献类型：
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作者：
Mukhopadhyay, D;Jung, J;Anant, S
基因表达的转录后调控在调节经历凋亡的细胞中的基因表达中起关键作用。环氧合酶-2（考克斯-2）是花生四烯酸转化为前列腺素E2（PGE（2））的关键酶，在许多类型的腺癌中显著上调。考克斯-2过表达导致PGE 2产生增加，导致细胞增殖增加。PGE 2增强细胞对电离辐射的抵抗力。因此，了解调节考克斯-2表达的机制可能会导致重要的治疗进展。除了转录调控外，考克斯-2的表达还受到mRNA稳定性和翻译的显著调节。我们以前已经证明，RNA结合蛋白CUGBP 2结合AU丰富的序列来调节考克斯-2 mRNA的翻译。在目前的研究中，我们已经确定，考克斯-2 mRNA和CUGBP 2 mRNA的表达诱导MCF-7细胞，乳腺癌细胞系，暴露于12戈伊射线。然而，只有CUGBP 2蛋白被诱导，但考克斯-2蛋白水平没有改变。沉默RNA（siRNA）介导的CUGBP 2抑制逆转了考克斯-2蛋白表达的阻断。此外，MCF-7细胞因辐射损伤而发生凋亡，这也被CUGBP 2 siRNAs逆转。这些数据表明，CUGBP 2是乳腺癌细胞对遗传毒性损伤的凋亡反应的关键调节因子。
Posttranscriptional control of gene expression plays a key role in regulating gene expression in cells undergoing apoptosis. Cyclooxygenase-2 (COX-2) is a crucial enzyme in the conversion of arachidonic acid to prostaglandin E2 (PGE(2)) and is significantly upregulated in many types of adenocarcinomas. COX-2 overexpression leads to increased PGE2 production, resulting in increased cellular proliferation. PGE2 enhances the resistance of cells to ionizing radiation. Accordingly, understanding mechanisms regulating COX-2 expression may lead to important therapeutic advances. Besides transcriptional control, COX-2 expression is significantly regulated by mRNA stability and translation. We have previously demonstrated that RNA binding protein CUGBP2 binds AU-rich sequences to regulate COX-2 mRNA translation. In the current study, we have determined that expression of both COX-2 mRNA and CUGBP2 mRNA are induced in MCF-7 cells, a breast cancer cell line, following exposure to 12 Gy gamma-irradiation. However, only CUGBP2 protein is induced, but COX-2 protein levels were not altered. Silencer RNA (siRNA)mediated inhibition of CUGBP2 reversed the block in COX-2 protein expression. Furthermore, MCF-7 cells underwent apoptosis in response to radiation injury, which was also reversed by CUGBP2 siRNAs. These data suggest that CUGBP2 is a critical regulator of the apoptotic response to genotoxic injury in breast cancer cells.