Transformation of mammary epithelial cells by 3-phosphoinositide- dependent protein kinase-1 activates beta-catenin and c-Myc, and down-regulates caveolin-1.
Transformation of mammary epithelial cells by 3-phosphoinositide- dependent protein kinase-1 activates beta-catenin and c-Myc, and down-regulates caveolin-1.
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发表时间：
2003-09
期刊：
影响因子：
11.2
通讯作者：
Zhihui Xie;Xiao Zeng;T. Waldman;R. Glazer
中科院分区：
文献类型：
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作者：
Zhihui Xie;Xiao Zeng;T. Waldman;R. Glazer
3-磷酸肌醇依赖性蛋白激酶-1 (PDK1) 在生长因子受体信号传导与肿瘤细胞增殖、存活和侵袭的耦合中发挥着关键作用。之前发现蛋白激酶 C (PKC) α（而非 Akt1）位于 PDK1 介导的乳腺上皮细胞转化的下游。为了确定其致癌活性的基础，对乳腺上皮细胞中 PDK1 介导的信号转导途径进行了研究。 β-连环蛋白/T 细胞因子依赖性启动子活性在 PDK1 和 PKCα 表达细胞中显着激活，但在 Akt1 表达细胞中未显着激活，这导致 β-连环蛋白/T 细胞因子靶基因 c-myc 和细胞周期蛋白 D1 水平升高。相比之下，caveolin-1 的转录被 c-myc 抑制，在表达 PDK1 和 PKCα 的细胞中下调，但在表达 Akt1 的细胞中则没有下调。对 16 种乳腺癌细胞系的分析表明，与乳腺上皮细胞相比，caveolin-1 表达缺失或减少，并且所有细胞系中的 PDK1 均升高。有趣的是，所有已知具有侵袭性的细胞系都在一定程度上表达了caveolin-1，而6个非侵袭性细胞系中有5个不表达caveolin-1。因此，c-myc 功能的同时增强和 Caveolin-1 的丧失或减少似乎是 PDK1 和 PKCα 介导的乳腺肿瘤发生的主要决定因素。
3-phosphoinositide-dependent protein kinase-1 (PDK1) plays a pivotal role in coupling growth factor receptor signaling to tumor cell proliferation, survival, and invasion. Protein kinase C (PKC) alpha, but not Akt1, was found previously to be downstream of PDK1-mediated transformation of mammary epithelial cells. To determine the basis for its oncogenic activity, signal transduction pathways mediated by PDK1 in mammary epithelial cells were investigated. beta-Catenin/T-cell factor-dependent promoter activity was markedly activated in PDK1- and PKCalpha-expressing cells, but not in Akt1-expressing cells, which resulted in increased levels of the beta-catenin/T-cell factor target genes c-myc and cyclin D1. In contrast, caveolin-1, of which the transcription is suppressed by c-myc, was down-regulated in PDK1- and PKCalpha-expressing, but not in Akt1-expressing cells. Analysis of 16 breast cancer cell lines established that caveolin-1 expression was either absent or reduced compared with breast epithelial cells, and that PDK1 was elevated in all of the cell lines. Interestingly, all of the cell lines known to be invasive expressed caveolin-1 to some degree, whereas, 5 of 6 cell lines that are not invasive did not express caveolin-1. Therefore, it appears that a concomitant gain of c-myc function and a loss or reduction of caveolin-1 are major determinants of PDK1- and PKCalpha-mediated mammary oncogenesis.