马达加斯加2
有丝分裂
生物
前中期
染色体不稳定性
非整倍体
主轴检查点
核分裂突变
诱导多能干细胞
细胞生物学
癌症研究
分子生物学
细胞周期
细胞周期检查点
主轴装置
遗传学
细胞分裂
细胞
染色体
胚胎干细胞
后期
基因
作者
Toshiaki Hitomi,Toshiyuki Habu,Hatasu Kobayashi,Hiroko Okuda,Kouji H. Harada,Kenji Osafune,Daisuke Taura,Masakatsu Sone,Isao Asaka,Tomonaga Ameku,Akira Watanabe,Tomoko Kasahara,Tomomi Sudo,Fumihiko Shiota,Hirokuni Hashikata,Yasushi Takagi,Daisuke Morito,Susumu Miyamoto,Kazuwa Nakao,Akio Koizumi
标识
DOI:10.1016/j.bbrc.2013.08.067
摘要
• Overexpression of RNF213 R4810K inhibited cell proliferation . • Overexpression of RNF213 R4810K had the time of mitosis 4-fold and mitotic failure. • R4810K formed a complex with MAD2 more readily than wild-type. • iPSECs from the MMD patients had elevated mitotic failure compared from the control. • RNF213 R4810K induced mitotic abnormality and increased risk of aneuploidy. Moyamoya disease (MMD) is a cerebrovascular disease characterized by occlusive lesions in the Circle of Willis. The RNF213 R4810K polymorphism increases susceptibility to MMD. In the present study, we characterized phenotypes caused by overexpression of RNF213 wild type and R4810K variant in the cell cycle to investigate the mechanism of proliferation inhibition. Overexpression of RNF213 R4810K in HeLa cells inhibited cell proliferation and extended the time of mitosis 4-fold. Ablation of spindle checkpoint by depletion of mitotic arrest deficiency 2 (MAD2) did not shorten the time of mitosis. Mitotic morphology in HeLa cells revealed that MAD2 colocalized with RNF213 R4810K. Immunoprecipitation revealed an RNF213/MAD2 complex: R4810K formed a complex with MAD2 more readily than RNF213 wild-type. Desynchronized localization of MAD2 was observed more frequently during mitosis in fibroblasts from patients ( n = 3, 61.0 ± 8.2%) compared with wild-type subjects ( n = 6, 13.1 ± 7.7%; p < 0.01). Aneuploidy was observed more frequently in fibroblasts ( p < 0.01) and induced pluripotent stem cells (iPSCs) ( p < 0.03) from patients than from wild-type subjects. Vascular endothelial cells differentiated from iPSCs (iPSECs) of patients and an unaffected carrier had a longer time from prometaphase to metaphase than those from controls ( p < 0.05). iPSECs from the patients and unaffected carrier had significantly increased mitotic failure rates compared with controls ( p < 0.05). Thus, RNF213 R4810K induced mitotic abnormalities and increased risk of genomic instability .
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