Myc deletion rescues Apc deficiency in the small intestine
Myc deletion rescues Apc deficiency in the small intestine
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DOI：
10.1038/nature05674
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发表时间：
2007-04-05
期刊：
影响因子：
64.8
通讯作者：
Clarke, Alan R.
中科院分区：
文献类型：
--
作者：
Sansom, Owen J.;Meniel, Valerie S.;Clarke, Alan R.
APC 基因编码腺瘤性息肉病大肠杆菌肿瘤抑制蛋白，其种系突变是家族性腺瘤性息肉病 (FAP)（一种常染色体肠癌综合征）的特征 (1)。 APC 失活也被认为是散发性结直肠癌发生过程中的关键早期事件 (2,3)，其缺失会导致 β-连环蛋白-Tcf4 转录复合物的组成型活性 (3)。原癌基因 c-MYC 已被确定为体外结直肠癌细胞 (4)、体内正常隐窝 (5) 以及因体内 APC 基因缺失而急性转化的肠上皮细胞 (6) 中 Wnt 通路的靶标；然而，其意义尚不清楚。因此，为了阐明Apc缺失后Myc在肠道中的作用，我们同时删除了成年小鼠小肠中的Apc和Myc。在这里，我们表明，Myc 的缺失挽救了 Apc 缺失时发生的分化、迁移、增殖和凋亡受到干扰的表型。值得注意的是，这种拯救是在高水平的核β-连环蛋白存在的情况下发生的。阵列分析表明，Myc 是 Apc 丢失后大部分 Wnt 靶基因激活所必需的。这些数据表明 Myc 是 Apc 丢失后肿瘤早期阶段的关键介质。
The APC gene encodes the adenomatous polyposis coli tumour suppressor protein, germline mutation of which characterizes familial adenomatous polyposis (FAP), an autosomal intestinal cancer syndrome(1). Inactivation of APC is also recognized as the key early event in the development of sporadic colorectal cancers(2,3), and its loss results in constitutive activity of the beta-catenin-Tcf4 transcription complex(3). The proto-oncogene c-MYC has been identified as a target of the Wnt pathway in colorectal cancer cells in vitro(4), in normal crypts in vivo(5) and in intestinal epithelial cells acutely transformed on in vivo deletion of the APC gene(6); however, the significance of this is unclear. Therefore, to elucidate the role Myc has in the intestine after Apc loss, we have simultaneously deleted both Apc and Myc in the adult murine small intestine. Here we show that loss of Myc rescued the phenotypes of perturbed differentiation, migration, proliferation and apoptosis, which occur on deletion of Apc. Remarkably, this rescue occurred in the presence of high levels of nuclear beta-catenin. Array analysis revealed that Myc is required for the majority of Wnt target gene activation following Apc loss. These data establish Myc as the critical mediator of the early stages of neoplasia following Apc loss.