The mitotic tensegrity guardian tau protects mammary epithelia from katanin-like1-induced aneuploidy.
The mitotic tensegrity guardian tau protects mammary epithelia from katanin-like1-induced aneuploidy.
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DOI：
10.18632/oncotarget.10728
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发表时间：
2016-08-16
期刊：
影响因子：
--
通讯作者：
Nakajima K
中科院分区：
文献类型：
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作者：
Sudo H;Nakajima K
微管相关蛋白tau已被确定为乳腺癌有效的阳性预后指标。为了探究tau蛋白在早期癌变中的生理功能，我们在原代培养的人乳腺上皮细胞中敲低内源性tau蛋白。这导致后期染色体桥接，随后微核，这两者都被进一步的katanin-like1敲低抑制。我们还发现外源性表达的katanin-like1诱导大鼠成纤维细胞转化被外源性tau阻止。在乳腺癌中发现的突变体katanin-like1 （L123V）显示出这种转化能力的增加以及对tau具有抗性的微管切断活性。tau蛋白的敲低导致tau蛋白正常定位的着丝点纤维的丢失。在分离的tau蛋白敲低的有丝分裂纺锤体中也观察到这种物理脆弱性，这支持了微管损伤与转化开始的相关性。tau基因敲低的细胞的核型显示一条X染色体丢失的频率增加，进一步表明tau基因参与了乳腺肿瘤的发生。我们提出tau可能通过保护纺锤体微管免受katanin-like1的过度切断而促进肿瘤进展。我们还提供数据表明，微管结合八肽NAP是针对肿瘤细胞中tau缺陷的候选修饰物。
The microtubule associated-protein tau has been identified as an effective positive prognostic indicator in breast cancer. To explore the physiological function of tau in early carcinogenesis, endogenous tau was knocked down in primary cultured human mammary epithelial cells. This resulted in chromosome-bridging during anaphase followed by micronucleation, both of which were suppressed by a further katanin-like1 knockdown. We also detected that the exogenously expressed katanin-like1 induction of cellular transformation is prevented by exogenous tau in rat fibroblasts. The mutant katanin-like1 (L123V) identified in breast cancer showed an increase in this transformation capacity as well as microtubule severing activity resistant to tau. The tau knockdown resulted in a loss of the kinetochore fibers on which tau is normally localized. This physical fragility was also observed in isolated tau-knockdown mitotic spindles, supporting the relevance of microtubule damage to the onset of transformation. The karyotyping of tau-knockdown cells showed increased frequency of loss of one X chromosome, further suggesting the involvement of tau in breast tumorigenesis. We propose that tau may contribute to tumor progression by protecting spindle microtubules from excess severing by katanin-like1. We also present data indicating that the microtubule-binding octapeptide NAP is a candidate modifier against the tau deficiency in tumor cells.