RAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora-A and BRCA2 in midbody during cytokinesis.
RAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora-A and BRCA2 in midbody during cytokinesis.
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RAS 通过胞质分裂过程中体中 Aurora-A 和 BRCA2 表达失衡诱导的基因组不稳定性来促进肿瘤发生。
DOI：
10.1002/ijc.28032
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发表时间：
2013-07-15
影响因子：
6.4
通讯作者：
Liu, Jinsong
中科院分区：
文献类型：
--
作者：
Yang, Gong;Mercado-Uribe, Imelda;Multani, Asha S.;Sen, Subrata;Shih, Ie-Ming;Wong, Kwong-Kwok;Gershenson, David M.;Liu, Jinsong
已知癌基因RAS诱导基因组不稳定性，导致癌症发展;然而，其潜在机制仍然知之甚少。为了更好地了解RAS的功能，我们测量了卵巢癌细胞系和含有RAS突变的肿瘤样本中功能相关基因Aurora-A和BRCA 2的活性。我们发现Aurora-A和BRCA 2通过调节胞质分裂和多倍化，反向控制RAS相关的基因组不稳定性和卵巢肿瘤发生。突变RAS的过度表达消除了BRCA 2的表达，但诱导了Aurora-A在中段的积累，导致异常的胞质分裂，并最终通过癌细胞中的多倍性导致染色体不稳定。RAS通过法尼基蛋白转移酶β（FTβ）和胰岛素样生长因子结合蛋白3（IGFBP-3）的蛋白表达失调来调节Aurora-A和BRCA 2的表达。我们的研究结果表明，Aurora-A和BRCA 2表达的不平衡调节RAS诱导的基因组不稳定性和肿瘤发生。
The oncogene RAS is known to induce genomic instability, leading to cancer development; the underlying mechanism, however, remains poorly understood. To better understand how RAS functions, we measured the activity of the functionally related genes Aurora-A and BRCA2 in ovarian cancer cell lines and tumor samples containing RAS mutations. We found that Aurora-A and BRCA2 inversely controlled RAS-associated genomic instability and ovarian tumorigenesis through regulation of cytokinesis and polyploidization. Over-expression of mutated RAS ablated BRCA2 expresson but induced Aurora-A accumulation at the midbody, leading to abnormal cytokinesis and ultimately chromosomal instability via polyploidy in cancer cells. RAS regulates the expression of Aurora-A and BRCA2 through dysregulated protein expression of farnesyl protein transferase β (FTβ and insulin-like growth factor binding protein 3 (IGFBP-3). Our results suggest that the imbalance in expression of Aurora-A and BRCA2 regulates RAS-induced genomic instability and tumorigensis.
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DOI：
10.1073/pnas.87.24.9665
发表时间：
1990-12-01
影响因子：
11.1
作者：
GOODMAN, LE;JUDD, SR;TAMANOI, F
通讯作者：
TAMANOI, F
影响因子：
56.9
作者：
Daniels, MJ;Wang, YM;Venkitaraman, AR
通讯作者：
Venkitaraman, AR
影响因子：
4.8
作者：
Martin, JL;Baxter, RC
通讯作者：
Baxter, RC
影响因子：
4.8
作者：
Moro, Loredana;Arbini, Arnaldo A.;Greco, Margherita
通讯作者：
Greco, Margherita
影响因子：
64.8
作者：
Macurek, Libor;Lindqvist, Arne;Medema, Rene H.
通讯作者：
Medema, Rene H.