Wnt pathway mutations selected by optimal β-catenin signaling for tumorigenesis
Wnt pathway mutations selected by optimal β-catenin signaling for tumorigenesis
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DOI：
10.1016/j.febslet.2006.05.053
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发表时间：
2006-06-26
期刊：
影响因子：
3.5
通讯作者：
Sung, Myong-Hee
中科院分区：
文献类型：
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作者：
Cho, Kwang-Hyun;Baek, Songjoon;Sung, Myong-Hee
据观察，Wnt/β-连环蛋白通路成分的突变是大多数结直肠肿瘤的最早起始事件。大多数突变发生在抑癌腺瘤性息肉病大肠杆菌 (APC) 中，尽管还有其他基因能够调节该通路的活性。此外，与结肠癌相关的特定 APC 突变表明肿瘤可能选择某些截短形式的 APC，部分保留其功能，即抑制 β-连环蛋白。我们使用最近构建的 Wnt 通路数学模型来估计 APC 和其他已知突变中各种突变的影响，该数学模型是为代表保守的核心分子事件而构建的。我们提供的证据表明，APC 突变的选择不是基于 P-连环蛋白的最大水平，而是基于似乎对组织特异性肿瘤发生最佳的不同活性状态。这个最佳水平是通过平衡 P-连环蛋白信号传导和 Axin2 的诱导来确定的，Axin2 充当有效的负反馈。 APC 突变的主要模式可能提供促进结直肠肿瘤发生的协同致癌作用：细胞存活和更新的最佳信号传导、破坏的细胞粘附、染色体不稳定性和改变干细胞的不对称分裂。 (c) 2006 年由 Elsevier B.V. 代表欧洲生化学会联合会出版。
Mutations in components of the Wnt/beta-catenin pathway are observed to be the earliest initiating event for most colorectal tumors. The majority of the mutations occur in the tumor suppressor adenomatous polyposis coli (APC), even though there are other genes that are capable of modulating the pathway activity. Moreover, the specific APC mutations associated in colon cancer indicate the possibility that the tumor selects for certain truncated forms of APC that partially retain its function, namely, inhibition of beta-catenin. We estimated the effects of various mutations in APC and other known mutations using a recent mathematical model of the Wnt pathway that was constructed to represent the conserved core molecular events. We provide evidence that APC mutations are selected not based on the maximal level of P-catenin but rather based on distinct state of activity that appears to be optimal for the tissue-specific tumorigenesis. This optimal level is determined by balancing P-catenin signaling and the induction of Axin2 that acts as a potent negative feedback. The predominant pattern of APC mutations may provide synergistic oncogenic effects that promote colorectal tumorigenesis: the optimal signaling for cell survival and renewal, disrupted cell adhesion, chromosomal instability, and altered asymmetric division of stem cells. (c) 2006 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.