The Apc1322T Mouse Develops Severe Polyposis Associated With Submaximal Nuclear β-Catenin Expression
The Apc1322T Mouse Develops Severe Polyposis Associated With Submaximal Nuclear β-Catenin Expression
复制标题
DOI：
10.1053/j.gastro.2009.02.058
复制
发表时间：
2009-06-01
期刊：
影响因子：
29.4
通讯作者：
Tomlinson, Ian
中科院分区：
文献类型：
--
作者：
Pollard, Patrick;Deheragoda, Maesha;Tomlinson, Ian
背景和目标：我们先前证明了人类结直肠肿瘤中的2个APC突变是共同选择的，因为肿瘤发生需要最佳水平的Wnt信号传导。我们和其他人随后发现，结直肠肿瘤中截短的APC蛋白通常保留总共1-2个β-连环蛋白结合/降解重复序列（20 AAR）;很少有肠道肿瘤的蛋白质没有20 AAR。APC的“2个命中”的共选择使得难以在人类中进行该领域的进一步机制研究。然而，在小鼠中，第二次命中似乎随所使用的品系或遗传背景而变化。这表明在小鼠中产生次优Apc基因型的可能性。方法：我们构建了一个保留20 AAR突变蛋白的小鼠Apc（1322 T）。在与C57 BL/6 J背景重复回交后，我们将1322 T动物与广泛使用的Min小鼠进行了比较，在Min小鼠中突变的Apc蛋白具有0个20 AAR。结果：在这两种小鼠中，肠腺瘤表现出拷贝中性杂合性丢失，使它们成为突变型Apc等位基因的纯合型。1322 T动物的息肉病明显更严重，具有更早发作、更大、更多和更严重的发育不良腺瘤。1322 T肿瘤也具有更显著的潘氏细胞分化和更高频率的隐窝分裂。令人惊讶的是，1322 T肿瘤细胞核β-连环蛋白表达低于Min肿瘤。结论：我们认为Apc（1322 T）突变产生次最大β-连环蛋白水平，比Apc（Min）突变更有效地促进早期肿瘤生长。
Background & Aims: We previously demonstrated that the 2 APC mutations in human colorectal tumors are coselected, because tumorigenesis requires an optimal level of Wnt signaling. We and others subsequently showed that the truncated APC proteins in colorectal tumors usually retain a total of 1-2 beta-catenin binding/degradation repeats (20AARs); very few intestinal tumors have proteins with no 20AARs. The coselection of the "2 hits" at APC makes it difficult to undertake further mechanistic studies in this area in humans. In mice, however, second hits appear to vary with the strain or genetic background used. This suggested the possibility of creating suboptimal Apc genotypes in the mouse. Methods: We have constructed a mouse, Apc(1322T), with a mutant protein retaining one 20AAR. After repeated backcrossing to the C57BL/6J background, we compared the 1322T animals with the widely used Min mouse in which the mutant Apc protein has zero 20AARs. Results: In both mice, intestinal adenomas showed copy-neutral loss of heterozygosity, making them homozygous for the mutant Apc allele. 1322T animals had markedly more severe polyposis, with earlier-onset, larger, more numerous, and more severely dysplastic adenomas. 1322T tumors also had more marked Paneth cell differentiation and higher frequencies of crypt fission. Somewhat surprisingly, nuclear beta-catenin expression was lower in 1322T than Min tumors. Conclusions: We propose that the Apc(1322T) mutation produces submaximal beta-catenin levels that promote early tumor growth more effectively than the Apc(Min) mutation.