有丝分裂停滞缺陷 1（基因名称 MAD1L1）是有丝分裂纺锤体组装检查点的重要组成部分，在结肠癌中经常过度表达，这与较差的无病生存率相关。 MAD1 上调会诱导组织培养细胞中与肿瘤促进相关的两种表型——低染色体不稳定 (CIN) 率和肿瘤抑制因子 p53 的不稳定。使用 CRISPR/Cas9 基因编辑，我们通过将多西环素 (dox) 诱导型启动子和 HA 标签插入内源性小鼠 Mad1l1 基因中，生成了一种新型小鼠模型，在存在反向条件的情况下暴露于 dox 后，能够诱导 HA-MAD1 的表达tet 反式激活因子 (rtTA)。小鼠结肠中 MAD1 适度过度表达 2 倍，导致 p53 表达减少，有丝分裂缺陷增加，与 CIN 一致。在接触结肠特异性炎症剂葡聚糖硫酸钠 (DSS) 后，31% 的小鼠出现结肠病变，包括粘液性腺癌，而对照组动物则没有形成结肠病变。雄性小鼠的病变发生率特别高，其中 57% 的结肠中至少出现一处增生性息肉、腺瘤或腺癌。值得注意的是，表达 HA-MAD1 的小鼠也在 DSS 预计不会诱发炎症的组织中出现病变。这些发现表明，MAD1 上调足以促进免疫活性小鼠炎症情况下结肠肿瘤的发生。版权所有：© 2024 Copeland 等人。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

Mitotic Arrest Deficient 1 (gene name MAD1L1), an essential component of the mitotic spindle assembly checkpoint, is frequently overexpressed in colon cancer, which correlates with poor disease-free survival. MAD1 upregulation induces two phenotypes associated with tumor promotion in tissue culture cells-low rates of chromosomal instability (CIN) and destabilization of the tumor suppressor p53. Using CRISPR/Cas9 gene editing, we generated a novel mouse model by inserting a doxycycline (dox)-inducible promoter and HA tag into the endogenous mouse Mad1l1 gene, enabling inducible expression of HA-MAD1 following exposure to dox in the presence of the reverse tet transactivator (rtTA). A modest 2-fold overexpression of MAD1 in murine colon resulted in decreased p53 expression and increased mitotic defects consistent with CIN. After exposure to the colon-specific inflammatory agent dextran sulfate sodium (DSS), 31% of mice developed colon lesions, including a mucinous adenocarcinoma, while none formed in control animals. Lesion incidence was particularly high in male mice, 57% of which developed at least one hyperplastic polyp, adenoma or adenocarcinoma in the colon. Notably, mice expressing HA-MAD1 also developed lesions in tissues in which DSS is not expected to induce inflammation. These findings demonstrate that MAD1 upregulation is sufficient to promote colon tumorigenesis in the context of inflammation in immune-competent mice.Copyright: © 2024 Copeland et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.