Survivin splice variants are not essential for mitotic progression or inhibition of apoptosis induced by doxorubicin and radiation.
Survivin splice variants are not essential for mitotic progression or inhibition of apoptosis induced by doxorubicin and radiation.
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DOI：
10.2147/ott.s28147
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发表时间：
2012
影响因子：
4
通讯作者：
Chakravarti A
中科院分区：
文献类型：
--
作者：
Jacob NK;Cooley JV;Shirai K;Chakravarti A
生存素是有丝分裂的关键调节因子，并且是几乎所有癌症中过表达的细胞凋亡抑制剂。在目前的研究中，正常增殖的人脐静脉内皮细胞，前列腺癌和肺癌细胞系表达不同水平的生存素及其剪接变异体的细胞周期概况进行了比较，使用一种新的功能互补分析。当外源性表达水平与内源性全长生存素相当时，内源性生存素缺失后观察到的染色体分离和胞质分裂缺陷未得到任何生存素剪接变体的补充：生存素-2B、生存素-3B、生存素-Δ Ex 3或生存素-2A。在内源性蛋白水平上未检测到Survivin变体。具有较高水平的全长存活素和存活素-2B表达的癌细胞在阿霉素处理和辐射后表现出减少的半胱天冬酶-3活化。虽然早期的研究集中在癌细胞特异性生存素的功能和表达水平，但目前的研究提出了生存素在正常分裂细胞中的重要作用。发现全长生存素与染色体乘客复合物中的Aurora-B激酶相关，并且在癌症以及正常增殖细胞中，在Aurora-B激酶抑制后观察到生存素的耗竭模拟有丝分裂表型。因此，我们的研究将生存素确定为增殖的标志物，而不是癌症特异性标志物。因此，靶向生存素的系统性治疗干预将影响癌症以及正常增殖细胞。
Survivin is a critical regulator of mitosis, and an inhibitor of apoptosis which is overexpressed in almost all cancers. In the current study, cell cycle profiles of normal proliferating human umbilical vein endothelial cells, prostate cancer, and lung cancer cell lines expressing varying levels of survivin and its splice variants were compared using a novel functional complementation assay. Defects in chromosome segregation and cytokinesis that were observed after depletion of endogenous survivin were not complemented by any of the survivin splice variants: survivin-2B, survivin-3B, survivin-ΔEx3, or survivin-2A when expressed exogenously at a level comparable to endogenous full-length survivin. Survivin variants were not detectable at the endogenous protein level. Cancer cells with higher levels of full-length survivin and survivin-2B expression, exhibited reduced caspase-3 activation following doxorubicin treatment and radiation. Whereas earlier studies focused on function and expression levels of survivin specific to cancer cells, the current study brings forward the essential role of survivin in normal dividing cells. Full-length survivin was found to be associated with Aurora-B kinase in the chromosomal passenger complex and depletion of survivin mimics mitotic phenotypes observed after Aurora-B kinase inhibition, in cancer as well as normal proliferating cells. Thus, our study establishes survivin as a marker of proliferation, rather than a cancer specific marker. Therefore, systemic therapeutic interventions targeting survivin will affect cancer as well as normal proliferating cells.