A novel apoptotic pathway induced by the drs tumor suppressor gene
A novel apoptotic pathway induced by the drs tumor suppressor gene
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DOI：
10.1038/sj.onc.1207419
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发表时间：
2004-04
期刊：
影响因子：
8
通讯作者：
Y. Tambe;T. Isono;S. Haraguchi;Atsuko Yoshioka-Yamashita;M. Yutsudo;H. Inoue
中科院分区：
文献类型：
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作者：
Y. Tambe;T. Isono;S. Haraguchi;Atsuko Yoshioka-Yamashita;M. Yutsudo;H. Inoue
drs基因最初是作为v-src转化的抑制基因分离的。在多种人类癌细胞系和组织中，drs mRNA的表达显著下调，表明drs基因具有抑癌作用。在这项研究中，我们发现，异位表达的Drs蛋白诱导人癌细胞系的凋亡。使用drs的缺失突变体的分析表明，C-末端区域和N-末端区域中的三个一致重复序列对于诱导细胞凋亡是必不可少的。Caspase-12、caspase-9和caspase-3被drs依次激活，caspase-3和caspase-9的特异性抑制剂抑制drs诱导的细胞凋亡。在drs诱导的细胞凋亡中没有观察到细胞色素c从线粒体释放到细胞质中，这表明线粒体途径不介导drs诱导的细胞凋亡。此外，我们发现Drs蛋白可以与ASY/Nogo-B/RTN-x S相互作用，ASY/Nogo-B/RTN-x S是一种位于内质网的凋亡诱导蛋白，这些基因的共表达增加了凋亡的效率。这些结果表明，Drs通过ASY/Nogo-B/RTN-x S，caspase-12，-9和-3介导的新途径诱导细胞凋亡。
The drs gene was originally isolated as a suppressor against v-src transformation. Expression of drs mRNA was markedly downregulated in a variety of human cancer cell lines and tissues, suggesting that the drs gene acts as a tumor suppressor. In this study, we found that ectopic expression of the Drs protein induced apoptosis in human cancer cell lines. Analyses using deletion mutants of drs revealed that both the C-terminal region and the three consensus repeats in the N-terminal region are essential for the induction of apoptosis. Caspase-12,-9, and-3 were sequentially activated by drs, and specific inhibitors of caspase-3 and-9 suppressed drs-induced apoptosis. The release of cytochrome c from the mitochondria into the cytoplasm was not observed in apoptosis by drs, suggesting that the mitochondrial pathway does not mediate drs-induced apoptosis. Furthermore, we found that the Drs protein can interact with ASY/Nogo-B/RTN-x S, an apoptosis-inducing protein localized in the endoplasmic reticulum, and that coexpression of these genes increased the efficiency of apoptosis. These results indicated that Drs induces apoptosis by a novel pathway mediated by ASY/Nogo-B/RTN-x S, caspase-12,-9, and-3.