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

¹ Molecular Virology Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases and ² Infectious Disease Pathogenesis Section, Comparative Medicine Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland; and ³ Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Kuan-Teh Jeang, NIH, Building 4, Room 306, 9000 Rockville Pike, Bethesda, MD 20892-0460. Phone: 301-496-6680; Fax: 301-480-3686; E-mail: kj7e{at}nih.gov.

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]

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