Transcriptional abnormality of the hsMAD2 mitotic checkpoint gene is a potential link to hepatocellular carcinogenesis

MAD2 is localized to kinetochores of unaligned chromosomes, where it inactivates the anaphase-promoting complex/cyclosome, thus contributing to the production of a diffusible anaphase inhibitory signal. Disruption of MAD2 expression leads to defects in the mitotic checkpoint, chromosome missegregation, and tumorigenesis. However, the mechanism by which deregulation and/or abnormality of hsMAD2 expression remains to be elucidated. Here, we clone and analyze a ∼0.5 kb fragment upstream of hsMAD2 and show that this fragment acts as a strong promoter. Transcriptional dysfunction of hsMAD2 is frequently observed in hepatocellular carcinoma cells, and down-regulation of hsMAD2 protein expression is correlated with transcriptional silencing of the hsMAD2 promoter by hypermethylation. These results imply a relationship between transcriptional abnormality of this mitotic checkpoint gene and mitotic abnormality in human cancers.