Survivin splice variants regulate the balance between proliferation and cell death
Survivin splice variants regulate the balance between proliferation and cell death
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DOI：
10.1038/sj.onc.1208350
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发表时间：
2005-03-17
期刊：
影响因子：
8
通讯作者：
Altura, RA
中科院分区：
文献类型：
--
作者：
Caldas, H;Jiang, YY;Altura, RA
Survivin 是一种凋亡蛋白抑制剂，在调节细胞周期和有丝分裂中也发挥着关键作用。它在几乎所有人类恶性肿瘤中显着表达，而在大多数正常组织中低表达或不表达，表明它将成为癌症定向治疗的理想靶点。缺乏对生存素差异影响正常细胞和恶性细胞中细胞凋亡和细胞分裂的分子机制的了解，阻碍了临床使用安全有效的生存素拮抗剂的开发。我们表明，生存素的多种功能作用可以部分地通过其与肿瘤细胞中生存素剪接变体的异二聚化来解释。生存素和生存素-Delta Ex3 在线粒体内相互作用，可能抑制线粒体依赖性细胞凋亡。如果通过 siRNA 转染消除了所有存活蛋白形式的表达，则细胞会发生凋亡和有缺陷的细胞分裂。总的来说，我们提供了新的见解，表明针对特定的生存素亚型，而不是单独的生存素，可以选择性地有效地破坏肿瘤细胞。这些发现可能会对临床治疗生物制剂的设计产生重大影响。
Survivin is an inhibitor of apoptosis protein that also plays critical roles in regulating the cell cycle and mitosis. Its prominent expression in essentially all human malignancies, and low or absent expression in most normal tissues, suggests that it would be an ideal target for cancer-directed therapy. Impeding development of safe and effective survivin antagonists for clinical use is a lack of understanding of the molecular mechanisms by which survivin differentially affects apoptosis and cell division, in normal and malignant cells. We show that the diverse functional roles of survivin can be explained, in part, by its heterodimerization with survivin splice variants in tumor cells. Survivin and survivin-Delta Ex3 interact within the mitochondria where they may inhibit mitochondrial-dependent apoptosis. If the expression of all survivin forms is eliminated by siRNA transfections, cells undergo both apoptosis and defective cell division. Overall, we provide new insights suggesting that targeting specific survivin isoforms, rather than survivin alone, may selectively and effectively destroy tumor cells. These findings are likely to have a significant impact in the design of biologic agents for clinical therapy.