It is also consistent with other studies showing that arsenic induces SAC bypass and decreases Mad2 expression levels [33] and that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), suppresses the expression of Mad2 resulting in increasing CIN [34]. the effects of zinc chromate, a particulate Cr(VI) compound, on Cdc20 localization, protein expression and interactions. Our data show Cdc20 is usually a target for particulate Cr(VI). Chronic zinc chromate exposure altered Cdc20 kinetochore localization and reduced the conversation of phosphorylated Cdc20 with Mad2, which may underlie zinc chromate-induced SAC bypass. strong class=”kwd-title” Keywords: Hexavalent chromium, Zinc chromate, Cdc20, Mad2, Spindle assembly checkpoint, 4-Methylumbelliferone (4-MU) Spindle assembly checkpoint bypass Introduction Hexavalent chromium [Cr(VI)] is usually a known human lung carcinogen and the solubility of Cr(VI) plays an important role in its carcinogenicity [1C3]. Epidemiologic studies show a higher lung malignancy risk for particulate-Cr(VI)-uncovered workers [2], and experimental studies show that only particulate Cr(VI) compounds induce tumors in animal models and neoplastic transformation of cultured mouse embryo cells [2,4]. However, despite its potent carcinogenicity, the carcinogenic mechanism for Cr(VI) is usually poorly comprehended. Chromosome Instability (CIN) consisting of alterations of both chromosome number and structure is usually a hallmark of human lung malignancy [5]. Cell culture studies show that both particulate and soluble Cr(VI) compounds can induce CIN in human lung cells and that human bronchial epithelial cells malignantly transformed by Cr(VI) exhibit an aneuploid phenotype [6,7]. Further data show that mechanisms underlying Cr(VI)-induced numerical CIN involve centrosome amplification and bypass of the Spindle Assembly Checkpoint (SAC) [7,8]. The SAC functions as a quality control mechanism for accurate chromosome segregation during mitosis [9]. It delays anaphase until all chromosomes are correctly attached to the mitotic spindle. Bypassing the SAC can lead to chromosome missegregation and aneuploidy. We previously showed that chronic exposure to particulate Cr(VI) compounds prospects to SAC bypass manifested as centromere distributing, premature centromere division, and premature anaphase [7,8]. These metaphase disruptions occurred despite the presence of an intact, functioning SAC indicating that particulate Cr(VI) is able to bypass the induction of the SAC and allow metaphase cells premature access 4-Methylumbelliferone (4-MU) into anaphase. However, the mechanism that underlies how Cr(VI) exposure disrupts the SAC is usually unknown. The primary effector in the SAC is usually Cdc20, which is an essential activator of the anaphase promoting complex/cyclosome (APC/C). As a mitotic cell becomes organized in metaphase, Cdc20 is usually recruited and localized to the kinetochore and combined with the Mad2, BubR1 and Bub3, proteins into a mitotic checkpoint complex (MCC). This complex then prevents Cdc20 from activating APC/C, preventing the start of anaphase [10]. When a metaphase cell is ready to 4-Methylumbelliferone (4-MU) progress into anaphase, the MCC releases Cdc20 so it can bind and activate APC/C. Once activated, APC/Cubiquinates securin causing securin CDH5 to release separase, which then cleaves cohesin separating the chromatid armsand anaphase ensues. Data show that disrupting Cdc20 can lead to aneuploidy 4-Methylumbelliferone (4-MU) and malignancy. For example, alteration of Cdc20 expression is associated with impairment of the SAC and aneuploidy in malignancy [11]. Mutations or/and dysregulated expression of Cdc20, has been found in breast malignancy cells [12]. Loss of Mad2-Cdc20 interactions due to mutant Cdc20 promotes tumor formation in mice [13]. Myeloma cells are highly aneuploid and have very low levels of Cdc20 and Mad2 protein [14]. Female mice that express low level of Cdc20 produce aneuploid oocytes and embryos [15]. Cadmium, a human carcinogen, reduces Cdc20 protein levels leading to disruption of early mitosis progression [16]. However, the impact of Cr(VI) on Cdc20 has not been studied. Thus, this study decided the impact of Cr(VI).
