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Heterozygous Deletion of Mitotic Arrest–Deficient Protein 1 (MAD1) Increases the Incidence of Tumors in Mice

2007; American Association for Cancer Research; Volume: 67; Issue: 1 Linguagem: Inglês

10.1158/0008-5472.can-06-3326

1538-7445

Yoichi Iwanaga, Ya‐Hui Chi, Akiko Miyazato, Sergey Sheleg, Kerstin Haller, Jean‐Marie Péloponèse, Yan Li, Jerrold M. Ward, Robert Benezra, Kuan‐Teh Jeang,

Cancer-related Molecular Pathways

Abstract Mitotic arrest–deficient protein 1 (MAD1) is a component of the mitotic spindle assembly checkpoint. We have created a knockout mouse model to examine the physiologic consequence of reduced MAD1 function. Mad1+/− mice were successfully generated, but repeated paired mating of Mad1+/− with Mad1+/− mice failed to produce a single Mad1−/− animal, suggesting that the latter genotype is embryonic lethal. In aging studies conducted for >18 months, Mad1+/− mice compared with control wild-type (wt) littermates showed a 2-fold higher incidence of constitutive tumors. Moreover, 42% of Mad1+/− (P < 0.03), but 0% of wt, mice developed neoplasia after treatment with vincristine, a microtubule depolymerization agent. Mad1+/− mouse embryonic fibroblasts (MEF) were found to be more prone than wt cells to become aneuploid; Mad1+/−, but not wt, MEFs produced fibrosarcomas when explanted into nude mice. Our results indicate an essential MAD1 function in mouse development and correlate Mad1 haploinsufficiency with increased constitutive tumors. [Cancer Res 2007;67(1):160–6]