mTOR-dependent suppression of protein phosphatase 2A is critical for phospholipase D survival signals in human breast cancer cells
mTOR-dependent suppression of protein phosphatase 2A is critical for phospholipase D survival signals in human breast cancer cells
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DOI：
10.1074/jbc.m504192200
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发表时间：
2005-10-28
影响因子：
4.8
通讯作者：
Foster, DA
中科院分区：
文献类型：
--
作者：
Hui, L;Rodrik, V;Foster, DA
肿瘤进展的一个关键方面是克服默认凋亡程序的生存信号的产生。最近的研究表明，磷脂酶D活性升高会在乳腺癌和其他人类癌症中产生生存信号。我们在这里报告，在人乳腺癌细胞系MDA-MB-231中升高的磷脂酶D活性以哺乳动物雷帕霉素靶蛋白（mTOR）依赖的方式抑制了推定的肿瘤抑制蛋白磷酸酶2A的活性。增加MCF 7细胞中磷脂酶D活性也抑制蛋白磷酸酶2A活性。升高的磷脂酶D活性抑制蛋白磷酸酶2A与核糖体亚基S6激酶和真核起始因子4 E结合蛋白1的结合。据报道，SV 40小t抗原对蛋白磷酸酶2A的抑制对于用SV 40早期区基因转化人细胞至关重要。与蛋白磷酸酶2A在磷脂酶D存活信号中的关键作用一致，SV 40小t抗原或蛋白磷酸酶2A的药理学抑制恢复了因抑制磷脂酶D或mTOR而丢失的存活信号。阻断磷脂酶D信号还导致促凋亡蛋白BAD在蛋白磷酸酶2A去磷酸化位点Ser-112处的磷酸化减少。磷脂酶D抑制蛋白磷酸酶2A的能力鉴定了人细胞转化中新兴磷脂酶D/mTOR存活途径的关键靶标。
A critical aspect of tumor progression is the generation of survival signals that overcome default apoptotic programs. Recent studies have revealed that elevated phospholipase D activity generates survival signals in breast and perhaps other human cancers. We report here that the elevated phospholipase D activity in the human breast cancer cell line MDA-MB-231 suppresses the activity of the putative tumor suppressor protein phosphatase 2A in a mammalian target of rapamycin ( mTOR)-dependent manner. Increasing the phospholipase D activity in MCF7 cells also suppressed protein phosphatase 2A activity. Elevated phospholipase D activity suppressed association of protein phosphatase 2A with both ribosomal subunit S6-kinase and eukaryotic initiation factor 4E-binding protein 1. Suppression of protein phosphatase 2A by SV40 small t-antigen has been reported to be critical for the transformation of human cells with SV40 early region genes. Consistent with a critical role for protein phosphatase 2A in phospholipase D survival signals, either SV40 small t-antigen or pharmacological suppression of protein phosphatase 2A restored survival signals lost by the suppression of either phospholipase D or mTOR. Blocking phospholipase D signals also led to reduced phosphorylation of the pro-apoptotic protein BAD at the protein phosphatase 2A dephosphorylation site at Ser-112. The ability of phospholipase D to suppress protein phosphatase 2A identifies a critical target of an emerging phospholipase D/mTOR survival pathway in the transformation of human cells.