The 'just-right' signaling model:: APC somatic mutations are selected based on a specific level of activation of the β-catenin signaling cascade
The 'just-right' signaling model:: APC somatic mutations are selected based on a specific level of activation of the β-catenin signaling cascade
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DOI：
10.1093/hmg/11.13.1549
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发表时间：
2002-06-15
影响因子：
3.5
通讯作者：
Smits, R
中科院分区：
文献类型：
--
作者：
Albuquerque, C;Breukel, C;Smits, R
根据Knudson关于肿瘤发生的两次“击中”假说的经典解释，两次“击中”是独立的突变事件，其最终结果是肿瘤抑制功能的丧失。最近，已经表明APC（腺瘤性结肠息肉病）基因并不完全遵循该模型。家族性腺瘤性息肉病（FAP）息肉中第二次打击的位置和类型取决于生殖系突变的定位。体细胞命中的这种非随机分布被解释为在肿瘤形成期间选择更有利的突变的结果。然而，APC基因编码一种多功能蛋白，这种选择所基于的确切细胞功能尚不清楚。在这项研究中，我们分析了体细胞APC点突变和杂合性丢失（洛）在133结直肠腺瘤6例FAP患者。我们观察到，当生殖细胞突变导致截短的蛋白质没有任何的7个β-连环蛋白下调20个氨基酸的重复分布在中央域的APC，大多数相应的体细胞点突变保留一个或两个相同的20个氨基酸的重复，频率较低。相反，当生殖系突变导致截短的蛋白质保留一个20个氨基酸的重复序列时，大多数第二次命中会去除所有20个氨基酸的重复序列。后者通常通过等位基因丢失来实现。值得注意的是，与以前的观察相反，在生殖系APC突变保留两个这样的重复的患者中，大多数体细胞命中是位于上游的点突变（而不是洛），并且去除了所有的20个氨基酸的重复。这些结果表明选择APC基因型可能保留下调β-连环蛋白信号传导的一些活性。我们建议，这种选择过程的目的是在特定程度的β-连环蛋白信号最佳的肿瘤形成，而不是在其组成性激活删除所有的β-连环蛋白下调图案在APC。
According to the classical interpretation of Knudson's two-hit' hypothesis for tumorigenesis, the two 'hits' are independent mutation events, the end result of which is loss of a tumor suppressing function. Recently, it has been shown that the APC (adenomatous polyposis coli) gene does not entirely follow this model. Both the position and type of the second hit in familial adenomatous polyposis (FAP) polyps depend on the localization of the germline mutation. This non-random distribution of somatic hits has been interpreted as the result of selection for more advantageous mutations during tumor formation. However, the APC gene encodes for a multifunctional protein, and the exact cellular function upon which this selection is based is yet unknown. In this study, we have analyzed somatic APC point mutations and loss of heterozygosity (LOH) in 133 colorectal adenomas from six FAP patients. We observed that when germline mutations result in truncated proteins without any of the seven beta-catenin downregulating 20-amino-acid repeats distributed in the central domain of APC, the majority of the corresponding somatic point mutations retain one or, less frequently, two of the same 20-amino-acid repeats. Conversely, when the germline mutation results in a truncated protein retaining one 20-amino-acid repeat, most second hits remove all 20-amino-acid repeats. The latter is frequently accomplished by allelic loss. Notably, and in contrast to previous observations, in a patient where the germline APC mutation retains two such repeats, the majority of the somatic hits are point mutations (and not LOH) located upstream and removing all of the 20-amino-acid repeats. These results indicate selection for APC genotypes that are likely to retain some activity in downregulating beta-catenin signaling. We propose that this selection process is aimed at a specific degree of beta-catenin signaling optimal for tumor formation, rather than at its constitutive activation by deletion of all of the p-catenin downregulating motifs in APC.