Chromium induces chromosomal instability, which is partly due to deregulation of BubR1 and Emi1, two APC/C inhibitors

被引:15
作者
Hu, Liyan [1 ]
Liu, Xin [1 ]
Chervona, Yana [1 ]
Yang, Feikun [1 ]
Tang, Moon-shong [1 ]
Darzynkiewicz, Zbigniew [2 ]
Dai, Wei [1 ]
机构
[1] NYU, Langone Med Ctr, Dept Environm Med, Tuxedo Pk, NY USA
[2] New York Med Coll, Valhalla, NY 10595 USA
关键词
chromium; checkpoint; chromosome instability; APC/C; BubR1; Emi1; DOUBLE-STRAND BREAKS; MISMATCH REPAIR; CELLULAR MECHANISMS; OXIDATIVE STRESS; CR(VI) EXPOSURE; MITOTIC ARREST; CARCINOGENESIS; CHECKPOINT; PHOSPHORYLATION; ACTIVATION;
D O I
10.4161/cc.10.14.16310
中图分类号
Q2 [细胞生物学];
学科分类号
071013 [干细胞生物学];
摘要
Disruption of cell cycle checkpoints and interference with the normal cell cycle progression frequently result in cell death or malignant transformation. Hexavalent chromium [Cr(VI)] is a well-known carcinogen that has been implicated in the occurrence of many types of human malignancies, including lung cancer. However, the exact mechanism by which Cr(VI) causes malignant transformation in the lung remains unknown. We have demonstrated that chronic exposure to a non-cytotoxic concentration of Cr(VI) induced a variety of chromosomal abnormalities, including premature sister chromatid separation, chromosomal breakage and the presence of lagging/misaligned chromosomes. After treatment with nocodazole, both HeLa and normal lung bronchial epithelial cells were arrested at mitosis. However, Cr(VI) significantly compromised M-phase arrest induced by nocodazole. Cr(VI) suppressed BubR1 activation and reduced expression of Emi1, leading to an unscheduled activation of APC/C. Consistent with this observation, Cr(VI) treatment caused enhanced polyubiquitination of geminin during mitotic release while it deregulated the activity of Cdt1, a DNA replication licensing factor. Combined, these results suggest that Cr(VI)-induced chromosomal instability is partly due to a perturbation of APC/C activities, leading to chromosomal instability.
引用
收藏
页码:2373 / 2379
页数:7
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