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首页> 外文期刊>Oncogene >Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1
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Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1

机译：乳腺癌特异性基因1与有丝分裂检查点激酶BubR1相互作用

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The abnormal expression of breast cancer-specific gene 1 (BCSG1) in malignant mammary epithelial cells is highly associated with the development and progression of breast cancer. A series of in vitro and in vivo studies performed in our laboratory and others have demonstrated that BCSG1 expression significantly stimulates proliferation, invasion, and metastasis of breast cancer cells. However, currently little is known about how BCSG1 exerts its oncogenic functions. To elucidate the cellular mechanisms underlying the effects of BCSG1 in breast cancer cells, we used a yeast two-hybrid system to screen for proteins that could associate with BCSG1. Through this screening, we identified the mitotic checkpoint protein BubR1 as a novel binding partner of BCSG1. The specific association of BCSG1 with BubR1 in breast cancer cells was demonstrated by immunoprecipitation and GST pull-down assays. Intriguingly, experiments conducted in four different cell lines all showed that exogenous expressions of BCSG1 consistently reduce the cellular levels of the BubR1 protein without affecting BubR1 mRNA expression. The tendency of endogenous BCSG1 expression coinciding with lower BubR1 protein levels was also observed in seven out of eight breast cancer cell lines. We further showed that the reducing effect of BCSG1 on BubR1 protein expression could be prevented by treating BCSG1-transfected cells with MG-132, a selective 26S proteasome inhibitor, implying that the proteasome machinery may be involved in the BCSG1-induced reduction of the BubR1 protein. Accompanied with a reduction of BubR1 protein level, BCSG1 expression resulted in multinucleation of breast cancer cells upon treatment with spindle inhibitor nocodazole, indicating an impaired mitotic checkpoint. Taken together, our novel findings suggest that BCSG1 may accelerate the progression of breast cancer at least in part by compromising the mitotic checkpoint control through inactivation of BubR1.
机译：乳腺癌特异性基因1（BCSG1）在恶性乳腺上皮细胞中的异常表达与乳腺癌的发生发展密切相关。在我们实验室和其他实验室中进行的一系列体外和体内研究表明，BCSG1表达显着刺激了乳腺癌细胞的增殖，侵袭和转移。但是，目前对于BCSG1如何发挥其致癌功能知之甚少。为了阐明BCSG1在乳腺癌细胞中的作用的细胞机制，我们使用了酵母双杂交系统来筛选可能与BCSG1相关的蛋白质。通过此筛选，我们确定了有丝分裂检查点蛋白BubR1为BCSG1的新型结合伴侣。 BCSG1与BubR1在乳腺癌细胞中的特异性结合已通过免疫沉淀和GST下拉检测法得到证实。有趣的是，在四个不同细胞系中进行的实验均显示BCSG1的外源表达持续降低BubR1蛋白的细胞水平，而不影响BubR1 mRNA的表达。在八种乳腺癌细胞系中的七种中也观察到内源性BCSG1表达与BubR1蛋白水平降低相一致的趋势。我们进一步表明，通过用MG-132（一种选择性的26S蛋白酶体抑制剂）处理BCSG1转染的细胞，可以防止BCSG1对BubR1蛋白表达的降低作用，这意味着蛋白酶体机制可能参与了BCSG1诱导的BubR1还原。蛋白。伴随BubR1蛋白水平的降低，经梭形抑制剂诺考达唑治疗后，BCSG1表达导致乳腺癌细胞多核化，表明有丝分裂检查点受损。综上所述，我们的新发现表明，BCSG1可能至少部分地通过灭活BubR1损害了有丝分裂检查点的控制而加速了乳腺癌的发展。

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