Proteasomal degradation of Atoh1 by aberrant Wnt signaling maintains the undifferentiated state of colon cancer
Proteasomal degradation of Atoh1 by aberrant Wnt signaling maintains the undifferentiated state of colon cancer
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DOI：
10.1016/j.bbrc.2008.02.011
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发表时间：
2008-04-18
影响因子：
3.1
通讯作者：
Watanabe, Mamoru
中科院分区：
文献类型：
--
作者：
Aragaki, Mikayo;Tsuchiya, Kiichiro;Watanabe, Mamoru
Atoh1在肠道细胞分化中起着至关重要的作用。我们已经证明了它的人类同源Hath1蛋白是WNT-GSK3轴的靶点，导致人类结肠癌中蛋白酶体的降解。然而，Hath1降解对结肠癌未分化状态的贡献仍不清楚。在这项研究中，我们证明了突变的Hath1的结构性表达和GSK3抑制剂对Hath1蛋白的稳定都增加了MUC2的表达，MUC2是分化的杯状细胞的代表功能。这意味着Hath1蛋白的降解可能是维持结肠癌未分化状态所必需的，GSK3抑制剂有可能在癌症治疗中使用。(C)2008 Elsevier Inc.保留所有权利。
Atoh1 plays a crucial role in intestinal cell differentiation. We have demonstrated that its human homolog Hath1 protein is targeted by the Wnt-GSK3 axis, resulting in the proteasomal degradation in human colon cancer. However, the contribution of Hath1 degradation to the undifferentiated state of colon cancer remains unknown. In this study, we demonstrated that both constitutive expression of mutant Hath1 and stabilization of Hath1 protein by a GSK3 inhibitor in colon cancer cells increased the expression of MUC2 known as a representative function of differentiated goblet cells. This means that Hath1 protein degradation may be required for maintaining the undifferentiated state of colon cancers, and that GSK3 inhibitors have potential for use in cancer therapy. (C) 2008 Elsevier Inc. All rights reserved.