The role of the two splice variants and extranuclear pathway on Ki-67 regulation in non-cancer and cancer cells.
The role of the two splice variants and extranuclear pathway on Ki-67 regulation in non-cancer and cancer cells.
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DOI：
10.1371/journal.pone.0171815
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Battaglia G
中科院分区：
文献类型：
--
作者：
Chierico L;Rizzello L;Guan L;Joseph AS;Lewis A;Battaglia G
Ki-67是一种核蛋白，由于其特定的细胞周期依赖性表达谱，已被用于癌症诊断。在对Ki-67的表达水平进行量化和表征后，作为细胞周期的一个功能，我们发现该蛋白的两个主要剪接变体（即α和β）在非癌细胞和癌细胞的mRNA和蛋白水平上都受到不同的调节。我们能够将α变异蛋白的存在与细胞周期间期的进展联系起来。我们还观察到，不同的表达谱对应于非癌细胞和癌细胞的不同降解途径。此外，Ki-67在两种细胞类型中均通过蛋白酶体系统被持续调节和降解，表明Ki-67蛋白具有活性控制作用。然而，我们也观察到一个假定的Ki-67核外消除途径，它被运输到高尔基体。我们在剪接变体的不同表达方面的证据可能代表了癌症诊断和预后新靶点发展的里程碑。此外，Ki-67在核外的意外消除强烈表明，这种蛋白质也必须在“核盒”之外进行研究，正如迄今为止所认为的那样。
Ki-67 is a nuclear protein that has been used in cancer diagnostic because of its specific cell-cycle dependent expression profile. After quantifying and characterising the expression level of Ki-67, as a function of the cell cycle, we found out that the two main splice variants of the protein (i.e. α and β) are differently regulated in non-cancerous and cancerous cells both at mRNA and protein level. We were able to correlate the presence of the α variant of the protein with the progression through the interphase of cell cycle. We also observed that the different expression profiles correspond to different degradation pathways for non-cancerous and cancerous cells. Furthermore, Ki-67 is continuously regulated and degraded via proteasome system in both cell types, suggesting an active control of the protein. However we also observed a putative extranuclear elimination pathway of Ki-67 where it is transported to the Golgi apparatus. Our evidence in the different expression of the splice variants may represent a milestone for the development of new targets for cancer diagnostic and prognostic. Additionally, the unexpected extranuclear elimination of Ki-67 strongly suggests that this protein must be looked at also outside of the “nuclear box”, as thought to date.