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Role of a Novel Splice Variant of Mitotic Arrest Deficient 1 (MAD1), MAD1β, in Mitotic Checkpoint Control in Liver Cancer

¹ Liver Cancer and Hepatitis Research Laboratory and S.H. Ho Foundation Research Laboratories, and Departments of Pathology, ² Anatomy, and ³ Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

Requests for reprints: Irene O-L. Ng, Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Room 127B, University Pathology Building, Pokfulam, Hong Kong. Phone: 852-2855-3967; Fax: 852-2872-5197; E-mail: iolng{at}hkucc.hku.hk.

Key Words: Exon 4 • cytoplasmic localization • MAD2 • carcinogenesis • chromosomal instability

Loss of mitotic checkpoint contributes to chromosomal instability, leading to carcinogenesis. In this study, we identified a novel splicing variant of mitotic arrest deficient 1 (MAD1), designated MAD1β, and investigated its role in mitotic checkpoint control in hepatocellular carcinoma (HCC). The expression levels of human MAD1β were examined in hepatoma cell lines and human HCC samples. The functional roles of MAD1β in relation to the mitotic checkpoint control, chromosomal instability, and binding with MAD2 were assessed in hepatoma cell lines. On sequencing, MAD1β was found to have deletion of exon 4. It was expressed at both mRNA and protein levels in the nine hepatoma cell lines tested and was overexpressed in 12 of 50 (24%) human HCCs. MAD1β localized in the cytoplasm, whereas MAD1 was found in the nucleus. This cytoplasmic localization of MAD1β was due to the absence of a nuclear localization signal in MAD1. In addition, MAD1β was found to physically interact with MAD2 and sequester it in the cytoplasm. Furthermore, expression of MAD1β induced mitotic checkpoint impairment, chromosome bridge formation, and aberrant chromosome numbers via binding with MAD2. Our data suggest that the novel splicing variant MAD1β may have functions different from those of MAD1 and may play opposing roles to MAD1 in mitotic checkpoint control in hepatocarcinogenesis. [Cancer Res 2008;68(22):9194–201]