Tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G1 tetraploidy checkpoint function
Tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G1 tetraploidy checkpoint function
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DOI：
10.1038/sj.onc.1207623
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发表时间：
2004-07-08
期刊：
影响因子：
8
通讯作者：
Saya, H
中科院分区：
文献类型：
--
作者：
Iida, S;Hirota, T;Saya, H
染色体或有丝分裂纺锤体的缺陷激活纺锤体检查点，导致细胞周期在前期停滞。纺锤体检查点的长时间激活通常导致有丝分裂在短暂的有丝分裂停止后没有分离地退出，从而形成四倍体G(1)细胞。这些四倍体细胞通常通过激活p53/pRb途径被阻断进入随后的S期，这被称为G(1)四倍体检查点。果蝇疣肿瘤抑制因子的人类同源物，疣，是一种进化保守的丝氨酸-苏氨酸激酶，与人类肿瘤的发展有关。我们之前的研究表明，疣在控制有丝分裂过程中起着至关重要的作用，通过与肌动蛋白的调节因子zyxin形成调节复合体。在有丝分裂器上的悲叹集合。然而，在细胞周期中，疣何时被激活以及疣功能的丧失如何导致肿瘤发生尚未阐明。在这里，我们发现疣在哺乳动物细胞有丝分裂期间被激活，并且在Rat1成纤维细胞中激酶失活疣的过表达显著诱导有丝分裂延迟。这种延迟是由于纺锤体组装检查点的长时间激活造成的，并且经常伴随着有丝分裂滑移和四倍体的发展。得到的四倍体细胞随后取消G(1)四倍体检查点，进入S期，DNA含量达到8N。G(1)四倍体检查点的损伤是由于表达激酶失活的疣未能诱导p53表达而引起的。因此，疣通过其在有丝分裂过程和G(1)四倍体检查点的作用在维持倍性中起关键作用。
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 G(1) 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 G(1) 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. lament 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 G(1) tetraploidy checkpoint and entered S phase to achieve a DNA content of 8N. This impairment of G(1) 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 G(1) tetraploidy checkpoint.