Sampath Janardhan, Pelus Louis M
Department of Microbiology and Immunology, Indiana University School of Medicine, 950 West Walnut St, Indianapolis, IN 46202, USA.
Curr Drug Discov Technol. 2007 Oct;4(3):174-91. doi: 10.2174/157016307782109652.
Survivin, a member of the IAP family is an attractive target for cancer treatment due to it's over expression in most cancers and low or no expression in most differentiated adult tissues. Survivin expression is a poor prognostic marker in a number of cancers. Clinical trials are currently underway evaluating anti-sense oligonucleotides against Survivin, immunotherapy using Survivin primed dentritic cells and peptide mimics that block interaction of Survivin with Hsp90 resulting in loss of Survivin protein stability. Additional approaches using ribozymes against Survivin mRNA, or dominant-negative cDNA to block Survivin function are in pre-clinical stages. Like many genes, Survivin is alternately spliced and a number of new splice variants have recently been identified. Expression of some of these splice variants correlates with loss of steroid receptors as well as the tumor suppressor p53, in some cancers, suggesting that like wild-type Survivin, at least some of these splice variants may also have prognostic relevance. This review will focus on the current understanding of the function of Survivin splice variants and their expression and sub-cellular localization in normal and neoplastic tissues as well as critically evaluating the potential toxicity of the Survivin directed therapies and their predicted effect on the alternatively spliced Survivin isoforms.
生存素是凋亡抑制蛋白（IAP）家族的成员之一，因其在大多数癌症中过度表达，而在大多数分化成熟的成人组织中低表达或不表达，故而成为癌症治疗的一个有吸引力的靶点。在多种癌症中，生存素的表达是一个预后不良的标志物。目前正在进行临床试验，评估针对生存素的反义寡核苷酸、使用经生存素致敏的树突状细胞的免疫疗法以及能阻断生存素与热休克蛋白90（Hsp90）相互作用从而导致生存素蛋白稳定性丧失的肽模拟物。使用针对生存素mRNA的核酶或显性负性cDNA来阻断生存素功能的其他方法正处于临床前阶段。与许多基因一样，生存素也存在可变剪接，最近已鉴定出一些新的剪接变体。在某些癌症中，其中一些剪接变体的表达与类固醇受体以及肿瘤抑制因子p53的缺失相关，这表明与野生型生存素一样，这些剪接变体中至少有一些可能也具有预后相关性。本综述将聚焦于目前对生存素剪接变体功能的认识，以及它们在正常组织和肿瘤组织中的表达及亚细胞定位，同时批判性地评估针对生存素的治疗方法的潜在毒性及其对可变剪接的生存素异构体的预期影响。
