Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the Aα subunit gene
Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the Aα subunit gene
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DOI：
10.1038/sj.onc.1204059
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发表时间：
2001-01-04
期刊：
影响因子：
8
通讯作者：
Walter, G
中科院分区：
文献类型：
--
作者：
Ruediger, R;Pham, HT;Walter, G
蛋白磷酸酶2A（PP 2A）的A亚基由15个不相同的重复序列组成。催化C亚基结合C-末端重复序列11-15，调节B亚基结合N-末端重复序列1-10。最近，已经描述了A α亚基的四种癌症相关突变体：肺癌中的Glu 64-->Asp，乳腺癌中的Glu 64--> Gly，黑色素瘤中的Arg 418--> Trp，以及乳腺癌中的Delta 171-589，基于PP 2A的模型，我们预测Glu 64-->Asp和Glu 64-->Gly可能是B亚基结合缺陷型，而Arg 418-->Trp和Delta 171 - 589可能既不结合B亚基也不结合C亚基。我们通过定点突变获得了这些突变体，并测定了它们与不同形式的B亚基结合的能力结果表明，所有突变体在结合B或B和C亚基方面都是缺陷的。具体地，N-末端突变体Glu 64->Asp和Glu 64->Gly在B'方面是缺陷的，但在B、B”和C亚基结合方面是正常的，而C-末端突变体Arg 418->Trp和Delta 171-589既不结合B亚基也不结合C亚基，这些发现对于PP 2A作为肿瘤抑制剂的潜在作用的意义进行了讨论。
The A subunit of protein phosphatase 2A (PP2A) consists of 15 nonidentical repeats. The catalytic C subunit binds to C-terminal repeats 11-15 and regulatory B subunits bind to N-terminal repeats 1-10, Recently, four cancer-associated mutants of the A alpha subunit have been described: Glu64-->Asp in lung carcinoma, Glu64 --> Gly in breast carcinoma, Arg418 --> Trp in melanoma, and Delta 171-589 in breast carcinoma, Based on our model of PP2A, we predicted that Glu64-->Asp and Glu64-->Gly might be defective in B subunit binding, whereas Arg418-->Trp and Delta 171 - 589 might bind neither B nor C subunits, We generated these mutants by site-directed mutagenesis and assayed their ability to associate with different forms of B subunits (B, B', B") or with the catalytic C subunit, The results demonstrate that all mutants are defective in binding either B or B and C subunits, Specifically, the N-terminal mutants, Glu64-->Asp and Glu64-->Gly, are defective in B' but normal in B, B", and C subunit binding, whereas the C-terminal mutants Arg418-->Trp and Delta 171-589 bind none of the B subunits nor the C subunit, The implications of these findings with regard to the potential role of PP2A as a tumor suppressor are discussed.