Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice
Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice
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DOI：
10.1158/0008-5472.can-06-3326
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发表时间：
2007-01-01
期刊：
影响因子：
11.2
通讯作者：
Jeang, Kuan-Teh
中科院分区：
文献类型：
--
作者：
Iwanaga, Yoichi;Chi, Ya-Hui;Jeang, Kuan-Teh
有丝分裂抑制缺陷蛋白1 （MAD1）是有丝分裂纺锤体组装检查点的一个组成部分。我们创建了一个敲除小鼠模型来检查MAD1功能降低的生理后果。成功产生了Mad1（+/-）小鼠，但Mad1（+/-）与Mad1（+/-）小鼠的多次配对交配未能产生单个Mad1（-/-）小鼠，表明后者基因型具有胚胎致死性。在为期18个月的衰老研究中，Mad1（+/-）小鼠与对照野生型（wt）幼崽相比，构成性肿瘤的发病率高出2倍。此外，42%的Mad1（+/-）小鼠（P < 0.03）和0%的wt小鼠在用长春新碱（微管解聚剂）治疗后发生肿瘤。发现Mad1(+/-) -小鼠胚胎成纤维细胞（MEF）比wt细胞更容易变成非整倍体；Mad1(+/-)，而不是wt， mef在移植到裸鼠体内时产生纤维肉瘤。我们的研究结果表明，MAD1在小鼠发育过程中具有重要的功能，并将MAD1单倍体功能不足与构成性肿瘤的增加联系起来。
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.