Contribution of BubR1 to oxidative stress-induced aneuploidy in p53-deficient cells.
Contribution of BubR1 to oxidative stress-induced aneuploidy in p53-deficient cells.
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DOI：
10.1002/cam4.101
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发表时间：
2013-08
期刊：
影响因子：
4
通讯作者：
Maehara, Yoshihiko
中科院分区：
文献类型：
--
作者：
Ikawa-Yoshida, Ayae;Ando, Koji;Oki, Eiji;Saeki, Hiroshi;Kumashiro, Ryuichi;Taketani, Kenji;Ida, Satoshi;Tokunaga, Eriko;Kitao, Hiroyuki;Morita, Masaru;Maehara, Yoshihiko
DNA非整倍体在各种人类肿瘤中观察到，并且与纺锤体组装检查点（SAC）蛋白的异常表达有关。氧化应激（OS）导致DNA损伤和染色体不稳定，可能导致癌变。OS也被认为有助于非整倍体细胞的增加。然而，目前尚不清楚OS是如何参与SAC的调节，并有助于与非整倍体相关的致癌作用。在这里，我们表明，氧化剂（KBrO3）激活p53信号通路，并抑制SAC因子，BubR1和Mad2的表达，在人二倍体成纤维细胞MRC5细胞。这种抑制依赖于功能性p53和活性氧。在p53基因敲低的细胞中，KBrO3不抑制BubR1和Mad2的表达，并增加双核细胞和具有>4N DNA含量的细胞。BubR1而不是Mad2的下调抑制了KBrO3诱导的双核细胞和p53敲低细胞中DNA含量>4N的细胞，表明BubR1通过其SAC功能以外的机制促进了多倍化的增强。在182例胃癌组织中，当p53表达阳性时，BubR1表达显著增高，提示p53功能丧失（P = 0.0019）。p53阳性表达和BubR1高表达与DNA非整倍体显著相关（P = 0.0065）。这些观察结果表明，p53缺陷可能会导致失败的BubR1下调OS和p53缺陷和BubR1积累可能有助于胃癌的发生与非整倍体。我们发现，OS可以有助于多倍体细胞的出现时，p53是在正常的人成纤维细胞缺陷。重要的是，这种多倍化可以通过下调一种纺锤体组装检查点因子BubR1的表达来抑制。我们还发现，p53功能障碍和BubR1积累与胃癌标本中的非整倍体的程度密切相关，我们的数据表明，p53缺陷和BubR1积累可能有助于胃癌的发生与非整倍体。
DNA aneuploidy is observed in various human tumors and is associated with the abnormal expression of spindle assembly checkpoint (SAC) proteins. Oxidative stress (OS) causes DNA damage and chromosome instability that may lead to carcinogenesis. OS is also suggested to contribute to an increase in aneuploid cells. However, it is not clear how OS is involved in the regulation of SAC and contributes to carcinogenesis associated with aneuploidy. Here we show that an oxidant (KBrO3) activated the p53 signaling pathway and suppressed the expression of SAC factors, BubR1, and Mad2, in human diploid fibroblast MRC5 cells. This suppression was dependent on functional p53 and reactive oxygen species. In p53 knockdown cells, KBrO3 did not suppress BubR1 and Mad2 expression and increased both binucleated cells and cells with >4N DNA content. BubR1 and not Mad2 downregulation suppressed KBrO3-induced binucleated cells and cells with >4N DNA content in p53 knockdown cells, suggesting that BubR1 contributes to enhanced polyploidization by a mechanism other than its SAC function. In analysis of 182 gastric cancer specimens, we found that BubR1 expression was significantly high when p53 was positively stained, which indicates loss of p53 function (P = 0.0019). Moreover, positive staining of p53 and high expression of BubR1 in tumors were significantly correlated with DNA aneuploidy (P = 0.0065). These observations suggest that p53 deficiency may lead to the failure of BubR1 downregulation by OS and that p53 deficiency and BubR1 accumulation could contribute to gastric carcinogenesis associated with aneuploidy. We found that OS could contribute to the emergence of polyploid cells when p53 was deficient in normal human fibroblast cells. Importantly, this polyploidization could be suppressed by downregulating the expression of one spindle assembly checkpoint factor, BubR1. We also found that p53 dysfunction and BubR1 accumulation strongly correlate with the extent of aneuploidy in gastric cancer specimen and our data suggest that p53 deficiency and BubR1 accumulation could contribute to gastric carcinogenesis associated with aneuploidy.
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影响因子：
8
作者：
Incassati, A;Patel, D;McCance, DJ
通讯作者：
McCance, DJ
DOI：
10.1083/jcb.200507081
发表时间：
2006-02-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Baker DJ;Jeganathan KB;Malureanu L;Perez-Terzic C;Terzic A;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
6.6
作者：
Aylon Y;Oren M
通讯作者：
Oren M
影响因子：
5.7
作者：
Ando, Koji;Kakeji, Yosihiro;Maehara, Yoshihiko
通讯作者：
Maehara, Yoshihiko
影响因子：
2
作者：
Matsuura, S;Matsumoto, Y;Kajii, T
通讯作者：
Kajii, T