Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice

被引:146
作者
Iwanaga, Yoichi
Chi, Ya-Hui
Miyazato, Akiko
Sheleg, Sergey
Haller, Kerstin
Peloponese, Jean-Marie, Jr.
Li, Yan
Ward, Jerrold M.
Benezra, Robert
Jeang, Kuan-Teh
机构
[1] NIAID, Mol Microbiol Lab, Mol Virol Sect, NIH, Bethesda, MD 20892 USA
[2] NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, Div Intramural Res,NIH, Bethesda, MD 20892 USA
[3] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10021 USA
关键词
D O I
10.1158/0008-5472.CAN-06-3326
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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) litter-mates 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.
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页码:160 / 166
页数:7
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