Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch.
Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch.
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细胞周期停滞增强了具有扩展的聚谷氨酰胺延伸的截短的马查多-约瑟夫病基因产物的体外细胞毒性。
DOI：
10.1093/hmg/9.1.69
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发表时间：
2000
影响因子：
3.5
通讯作者：
I. Kanazawa
中科院分区：
文献类型：
--
作者：
T. Yoshizawa;Y. Yamagishi;N. Koseki;J. Goto;H. Yoshida;F. Shibasaki;S. Shoji;I. Kanazawa
Machado-Joseph病（MJD）是一种遗传性神经退行性疾病，由MJD基因编码的蛋白质ataxin-3中的多聚谷氨酰胺片段扩增引起。使用一系列缺失构建体表达共济失调蛋白-3片段与扩展的聚谷氨酰胺延伸，我们观察到聚集体的形成和细胞死亡在培养的BHK-21细胞。在血清饥饿培养条件下，N-末端截短型共济失调蛋白-3与扩增的多聚谷氨酰胺束的细胞毒性作用增强，其中细胞被阻滞在G（0）/G（1）期。p21（waf 1/cip 1/sdi 1）是一种细胞周期蛋白-Cdk抑制剂，可诱导细胞周期停滞在G（1）期，p21的共表达也增加了由突变型ataxin-3片段在BHK-21细胞中产生的细胞死亡易感性。与未分化的增殖PC 12细胞相比，神经生长因子处理的有丝分裂后神经元PC 12细胞对G（0）/G（1）期细胞死亡的敏感性增加。这些结果有力地表明，截短型共济失调蛋白-3与扩展的聚谷氨酰胺伸展的细胞毒性通过细胞周期停滞在G（0）/G（1）期而增强。突变型共济失调蛋白-3可赋予处于G（0）/G（1）期的细胞更高的细胞死亡易感性。
Machado-Joseph disease (MJD) is an inherited neurodegenerative disorder caused by the expansion of the polyglutamine stretch in the MJD gene-encoded protein, ataxin-3. Using a series of deletion constructs expressing ataxin-3 fragments with expanded polyglutamine stretches, we observed aggregate formation and cell death in cultured BHK-21 cells. The cytotoxic effect of N-terminal-truncated ataxin-3 with the expanded polyglutamine tract was enhanced under serum starvation culture, in which cells were arrested in the G(0)/G(1)phase. Coexpression of p21 (waf1/cip1/sdi1), a cyclin-Cdk inhibitor that induced cell cycle arrest in the G(1)phase, also increased the cell death susceptibility produced by the mutant ataxin-3 fragment in BHK-21 cells. The elevated susceptibility to cell death in the G(0)/G(1)phase was confirmed in nerve growth factor-treated, postmitotic neuronal PC12 cells compared with undifferentiated proliferating PC12 cells. These results strongly suggest that the cellular toxicity of truncated ataxin-3 with an expanded polyglutamine stretch is enhanced by cell cycle arrest in the G(0)/G(1)phase. Mutant ataxin-3 may confer a higher susceptibility to cell death on cells in the G(0)/G(1)phase.
影响因子：
11.2
作者：
C. Osborne;C. Osborne;D. Boldt;G. Clark;J. Trent
通讯作者：
C. Osborne;C. Osborne;D. Boldt;G. Clark;J. Trent
影响因子：
3.5
作者：
Cooper, JK;Schilling, G;Ross, CA
通讯作者：
Ross, CA
影响因子：
56.9
作者：
DiFiglia, M;Sapp, E;Aronin, N
通讯作者：
Aronin, N