title: Chromium induces chromosomal instability, which is partly due to deregulation of BubR1 and Emi1, two APC/C inhibitors.
abstract: 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.affiliation: Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, NY, USA.
authors.forename: Liyan
authors.initials: L
authors.lastname: Hu
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Yana
authors.initials: Y
authors.lastname: Chervona
authors.forename: Feikun
authors.initials: F
authors.lastname: Yang
authors.forename: Moon-shong
authors.initials: MS
authors.lastname: Tang
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Darzynkiewicz
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000633:toxicity; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D002857:Chromium / Q000633:toxicity*; D043171:Chromosomal Instability; D044783:F-Box Proteins / Q000378:metabolism*; D064248:Geminin; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D015739:Nocodazole / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D000970:Antineoplastic Agents; C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; C498960:FBXO5 protein, human; C577995:GMNN protein, human; D064248:Geminin; D002857:Chromium; C074702:chromium hexavalent ion; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D015739:Nocodazole