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 missegregati...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2004-12, Vol.64 (23), p.8666-8673
Main Authors: JEONG, Sook-Jung, SHIN, Hyun-Jin, KIM, So-Jung, HA, Geun-Hyoung, CHO, Bok-Im, BAEK, Kwan-Hyuck, KIM, Chang-Min, LEE, Chang-Woo
Format: Article
Language:English
Subjects:
Antineoplastic agents
Base Sequence
Biological and medical sciences
Calcium-Binding Proteins - biosynthesis
Calcium-Binding Proteins - genetics
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Cell Cycle Proteins
Cell Line, Tumor
Cloning, Molecular
DNA Methylation
Down-Regulation
Gene Expression Regulation, Neoplastic
Gene Silencing
HeLa Cells
Humans
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Mad2 Proteins
Medical sciences
Mitosis - genetics
Molecular Sequence Data
Pharmacology. Drug treatments
Promoter Regions, Genetic
Repressor Proteins
RNA, Messenger - biosynthesis
RNA, Messenger - genetics
Spindle Apparatus - genetics
Spindle Apparatus - physiology
Transcription, Genetic
Transfection
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Summary: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 approximately 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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-03-3455