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首页> 外文期刊>Oncogene >Tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G1 tetraploidy checkpoint function
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Tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G1 tetraploidy checkpoint function

机译：抑癌药WARTS通过调节有丝分裂进程和G1四倍体检查点功能来确保基因组完整性

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Defects in chromosomes or mitotic spindles activate the spindle checkpoint, resulting in cell cycle arrest at prometaphase. The prolonged activation of spindle checkpoint generally leads to mitotic exit without segregation after a transient mitotic arrest and the consequent formation of tetraploid G1 cells. These tetraploid cells are usually blocked to enter the subsequent S phase by the activation of p53/pRb pathway, which is referred to as the G1 tetraploidy checkpoint. A human homologue of the Drosophila warts tumor suppressor, WARTS, is an evolutionarily conserved serine–threonine kinase and implicated in development of human tumors. We previously showed that WARTS plays a crucial role in controlling mitotic progression by forming a regulatory complex with zyxin, a regulator of actin filament assembly, on mitotic apparatus. However, when WARTS is activated during cell cycle and how the loss of WARTS function leads to tumorigenesis have not been elucidated. Here we show that WARTS is activated during mitosis in mammalian cells, and that overexpression of a kinase-inactive WARTS in Rat1 fibroblasts significantly induced mitotic delay. This delay resulted from prolonged activation of the spindle assembly checkpoint and was frequently followed by mitotic slippage and the development of tetraploidy. The resulting tetraploid cells then abrogated the G1 tetraploidy checkpoint and entered S phase to achieve a DNA content of 8N. This impairment of G1 tetraploidy checkpoint was caused as a consequence of failure to induce p53 expression by expressing a kinase-inactive WARTS. WARTS thus plays a critical role in maintenance of ploidy through its actions in both mitotic progression and the G1 tetraploidy checkpoint.
机译：染色体或有丝分裂纺锤体中的缺陷激活纺锤体检查点，导致细胞周期停在前中期。纺锤体检查点的延长激活通常会导致有丝分裂退出，在短暂的有丝分裂停滞后发生分离，从而形成四倍体G1细胞。这些四倍体细胞通常通过激活p53 / pRb途径而被阻止进入随后的S期，这被称为G1四倍体检查点。果蝇疣抑癌药WARTS的人类同源物是一种进化上保守的丝氨酸-苏氨酸激酶，与人类肿瘤的发生有关。我们先前显示，WARTS通过在有丝分裂装置上与肌动蛋白丝装配体的调节剂zyxin形成调节复合物，从而在控制有丝分裂进程中发挥关键作用。但是，尚未阐明当WARTS在细胞周期中被激活以及WARTS功能丧失如何导致肿瘤发生时。在这里，我们显示WARTS在哺乳动物细胞的有丝分裂过程中被激活，并且Rat1成纤维细胞中激酶无活性WARTS的过表达显着诱导了有丝分裂延迟。这种延迟是由于纺锤体装配检查点的激活时间延长造成的，并经常伴随着有丝分裂滑移和四倍体的形成。然后将得到的四倍体细胞废除G1四倍体检查点并进入S期，以达到8N的DNA含量。 G1四倍体检查点的这种损伤是由于无法通过表达激酶失活的WARTS诱导p53表达而导致的。因此，WARTS通过在有丝分裂进程和G1四倍体检查点中起作用，在维持倍性中起着至关重要的作用。

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