The beta-catenin binding domain of adenomatous polyposis coli is sufficient for tumor suppression.
The beta-catenin binding domain of adenomatous polyposis coli is sufficient for tumor suppression.
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发表时间：
2000-03
期刊：
影响因子：
11.2
通讯作者：
I. Shih;Jian Yu;T. He;B. Vogelstein;K. Kinzler
中科院分区：
文献类型：
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作者：
I. Shih;Jian Yu;T. He;B. Vogelstein;K. Kinzler
大肠腺瘤性息肉病(APC)基因失活是人类结直肠癌发生发展过程中的一个重要事件。在生化水平上，多结构域APC蛋白具有多种功能，但APC表达对细胞的影响以及它们与其生化功能的关系还不是很清楚。为了解决这些问题，我们产生了一种重组腺病毒(Ad-CBR)，它结构性地表达APC的中央三分之一，包括所有已知的β-连环蛋白结合重复序列。当在结肠癌细胞中表达时，Ad-CBR阻断了β-连环蛋白的核转位，并抑制了β-连环蛋白/Tcf-4介导的反式激活。相应地，APC/β-连环蛋白/Tcf-4途径的内源性靶点表达下调。携带野生型β-连环素的突变型APC的Ad-CBR感染结直肠癌细胞系后，细胞生长明显受阻，细胞发生凋亡。这些影响在野生型APC和突变的β-连环蛋白中减弱。这些发现表明，APC中央三分之一的β-连环蛋白结合域足以发挥其肿瘤抑制活性。
Inactivation of the adenomatous polyposis coli (APC) gene is a critical event in the development of human colorectal cancers. At the biochemical level, several functions have been assigned to the multidomain APC protein, but the cellular effects of APC expression and how they relate to its biochemical functions are less well defined. To address these issues, we generated a recombinant adenovirus (Ad-CBR) that constitutively expresses the central third of APC, which includes all of the known beta-catenin binding repeats. When expressed in colon cancer cells, Ad-CBR blocked the nuclear translocation of beta-catenin and inhibited beta-catenin/Tcf-4-mediated transactivation. Accordingly, expression of endogenous targets of the APC/beta-catenin/Tcf-4 pathway was down-regulated. Ad-CBR infection of colorectal cancer cell lines with mutant APC but wild-type beta-catenin resulted in substantial growth arrest followed by apoptosis. These effects were attenuated in lines with wild-type APC but with mutated beta-catenin. These findings suggest that the beta-catenin-binding domain in the central third of APC is sufficient for its tumor suppressor activity.