The APC tumour suppressor has a nuclear export function
The APC tumour suppressor has a nuclear export function
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DOI：
10.1038/35023016
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发表时间：
2000-08-31
期刊：
影响因子：
64.8
通讯作者：
Bienz, M
中科院分区：
文献类型：
--
作者：
Rosin-Arbesfeld, R;Townsley, F;Bienz, M
大肠腺瘤性息肉病（APC）蛋白在大多数结直肠肿瘤中发生突变(1)。几乎所有APC突变都是截断，其中许多终止于位于蛋白质中间的突变簇区域（2-4）。在表达APC突变体的癌细胞中，β -连环蛋白是稳定的（5,6），并易位到细胞核中，作为t细胞因子的转录共激活因子(7)。在正常发育过程中，APC也促进β -连环蛋白和犰狳果蝇的不稳定（8-11）。它通过与轴蛋白复合物结合来实现这一点，轴蛋白复合物通过蛋白酶体途径使β -连环蛋白/犰狳特异性降解（12）。APC在这一过程中起着调节作用（13,14），但人们对其了解甚少。在这里，我们发现APC包含高度保守的核输出信号3'，邻近突变簇区域，使其能够退出细胞核。这种能力在APC突变的癌细胞中丢失，我们提供的证据表明β -连环蛋白因此在细胞核中积累。因此，APC离开细胞核的能力似乎对其肿瘤抑制功能至关重要。
The adenomatous polpyposis coli (APC) protein is mutated in most colorectal tumours(1). Nearly all APC mutations are truncations, and many of these terminate in the mutation cluster region located halfway through the protein(2-4). In cancer cells expressing mutant APC, beta-catenin is stabilized(5,6) and translocates into the nucleus to act as a transcriptional co-activator of T-cell factor(7). During normal development, APC also promotes the destabilization of beta-catenin and Drosophila Armadillo(8-11). It does so by binding to the Axin complex which earmarks beta-catenin/Armadillo for degradation by the proteasome pathway(12). APC has a regulatory role in this process(13,14), which is poorly understood. Here we show that APC contains highly conserved nuclear export signals 3' adjacent to the mutation cluster region that enable it to exit from the nucleus. This ability is lost in APC mutant cancer cells, and we provide evidence that beta-catenin accumulates in the nucleus as a result. Thus, the ability of APC to exit from the nucleus appears to be critical for its tumour suppressor function.