Document Detail


Chromium induces chromosomal instability, which is partly due to deregulation of BubR1 and Emi1, two APC/C inhibitors.
MedLine Citation:
PMID:  21670593     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Liyan Hu; Xin Liu; Yana Chervona; Feikun Yang; Moon-shong Tang; Zbigniew Darzynkiewicz; Wei Dai
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-07-15
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  10     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-08-02     Completed Date:  2012-03-16     Revised Date:  2014-09-11    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2373-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenomatous Polyposis Coli Protein / metabolism*
Antineoplastic Agents / toxicity
Cell Cycle Proteins / metabolism*
Cell Division
Chromium / toxicity*
Chromosomal Instability*
F-Box Proteins / metabolism*
Geminin
HeLa Cells
Humans
Mitosis
Nocodazole / toxicity
Protein-Serine-Threonine Kinases / metabolism*
Ubiquitination
Grant Support
ID/Acronym/Agency:
CA090658/CA/NCI NIH HHS; ES000260/ES/NIEHS NIH HHS; ES010344/ES/NIEHS NIH HHS; R01 CA028704/CA/NCI NIH HHS; R01 CA028704-32/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/APC protein, human; 0/Adenomatous Polyposis Coli Protein; 0/Antineoplastic Agents; 0/CDT1 protein, human; 0/Cell Cycle Proteins; 0/F-Box Proteins; 0/FBXO5 protein, human; 0/GMNN protein, human; 0/Geminin; 0R0008Q3JB/Chromium; 18540-29-9/chromium hexavalent ion; EC 2.7.11.1/BUB1 protein, human; EC 2.7.11.1/Bub1 spindle checkpoint protein; EC 2.7.11.1/Protein-Serine-Threonine Kinases; SH1WY3R615/Nocodazole
Comments/Corrections

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