Constitutive phosphorylation of aurora-a on ser51 induces its stabilization and consequent overexpression in cancer.
Constitutive phosphorylation of aurora-a on ser51 induces its stabilization and consequent overexpression in cancer.
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DOI：
10.1371/journal.pone.0000944
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发表时间：
2007-09-26
期刊：
影响因子：
3.7
通讯作者：
Takata T
中科院分区：
文献类型：
--
作者：
Kitajima S;Kudo Y;Ogawa I;Tatsuka M;Kawai H;Pagano M;Takata T
丝氨酸/苏氨酸激酶Aurora-A(Aur-A)是一种在多种人类癌症中过度表达的原癌蛋白。Aur-A的过度表达被认为是由基因扩增或mRNA过度表达引起的。然而，最近的证据表明，在乳腺癌、胃癌、肝细胞癌和卵巢癌中，Aur-A的扩增和Aur-A的过表达之间存在差异。我们发现，侵袭性头颈癌表现出Aur-A蛋白的过度表达和稳定，而没有基因扩增或mRNA过度表达。在这里，我们测试了一种假说，即蛋白质破坏系统的异常会导致AUR-A在癌症中的积累和过度表达。Aur-A蛋白被APCCDh1泛素化，在细胞退出有丝分裂时降解，并在有丝分裂过程中观察到Ser51上Aur-A的磷酸化。Ser51上Aur-A的磷酸化抑制了APCCDh1介导的泛素化和随之而来的降解。有趣的是，在头颈部癌细胞中观察到Ser51的组成性磷酸化，并且蛋白质过表达和稳定。的确，在Aur-A蛋白过表达的头颈癌组织中观察到Ser51的磷酸化。此外，Aur-A Ser51磷酸模拟突变体在细胞周期进程中显示出蛋白质的稳定性，并增强了细胞转化的能力。广泛地说，这项研究发现了一种新的Aur-A在癌症中的过度表达模式，除了基因扩增和mRNA过度表达外，还通过磷酸化抑制其蛋白分解。我们认为，抑制Aur-A的磷酸化可能是降低肿瘤治疗中Aur-A水平的一种新方法。
The serine/threonine kinase Aurora-A (Aur-A) is a proto-oncoprotein overexpressed in a wide range of human cancers. Overexpression of Aur-A is thought to be caused by gene amplification or mRNA overexpression. However, recent evidence revealed that the discrepancies between amplification of Aur-A and overexpression rates of Aur-A mRNA were observed in breast cancer, gastric cancer, hepatocellular carcinoma, and ovarian cancer. We found that aggressive head and neck cancers exhibited overexpression and stabilization of Aur-A protein without gene amplification or mRNA overexpression. Here we tested the hypothesis that aberration of the protein destruction system induces accumulation and consequently overexpression of Aur-A in cancer. Aur-A protein was ubiquitinylated by APCCdh1 and consequently degraded when cells exited mitosis, and phosphorylation of Aur-A on Ser51 was observed during mitosis. Phosphorylation of Aur-A on Ser51 inhibited its APCCdh1-mediated ubiquitylation and consequent degradation. Interestingly, constitutive phosphorylation on Ser51 was observed in head and neck cancer cells with protein overexpression and stabilization. Indeed, phosphorylation on Ser51 was observed in head and neck cancer tissues with Aur-A protein overexpression. Moreover, an Aur-A Ser51 phospho-mimetic mutant displayed stabilization of protein during cell cycle progression and enhanced ability to cell transformation. Broadly, this study identifies a new mode of Aur-A overexpression in cancer through phosphorylation-dependent inhibition of its proteolysis in addition to gene amplification and mRNA overexpression. We suggest that the inhibition of Aur-A phosphorylation can represent a novel way to decrease Aur-A levels in cancer therapy.
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DOI：
10.1083/jcb.200309035
发表时间：
2004-01-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lindon C;Pines J
通讯作者：
Pines J
影响因子：
9.2
作者：
Carroll, CW;Enquist-Newman, M;Morgan, DO
通讯作者：
Morgan, DO
影响因子：
6.4
作者：
Miyoshi, Y;Iwao, K;Noguchi, S
通讯作者：
Noguchi, S
DOI：
10.1083/jcb.153.7.1381
发表时间：
2001-06-25
期刊：
The Journal of cell biology
影响因子：
--
作者：
Carrano AC;Pagano M
通讯作者：
Pagano M
影响因子：
10.5
作者：
Littlepage, LE;Ruderman, JV
通讯作者：
Ruderman, JV