Rosin-Arbesfeld R, Townsley F, Bienz M
Laboratory of Molecular Biology, Cambridge, UK.
Nature. 2000 Aug 31;406(6799):1009-12. doi: 10.1038/35023016.
The adenomatous polpyposis coli (APC) protein is mutated in most colorectal tumours. Nearly all APC mutations are truncations, and many of these terminate in the mutation cluster region located halfway through the protein. In cancer cells expressing mutant APC, beta-catenin is stabilized and translocates into the nucleus to act as a transcriptional co-activator of T-cell factor. During normal development, APC also promotes the destabilization of beta-catenin and Drosophila Armadillo. It does so by binding to the Axin complex which earmarks beta-catenin/Armadillo for degradation by the proteasome pathway. APC has a regulatory role in this process, 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.
腺瘤性结肠息肉病蛋白（APC）在大多数结直肠癌中发生突变。几乎所有的APC突变都是截短突变，其中许多突变终止于蛋白质中部的突变簇区域。在表达突变型APC的癌细胞中，β-连环蛋白被稳定化并转运至细胞核，作为T细胞因子的转录共激活因子发挥作用。在正常发育过程中，APC还能促进β-连环蛋白和果蝇的犰狳蛋白的不稳定。它通过与Axin复合体结合来实现这一点，该复合体将β-连环蛋白/犰狳蛋白标记为通过蛋白酶体途径降解。APC在这个过程中起调节作用，但对此了解甚少。在这里我们表明，APC在紧邻突变簇区域的3'端含有高度保守的核输出信号，使其能够从细胞核中输出。这种能力在APC突变癌细胞中丧失，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从细胞核中输出的能力似乎对其肿瘤抑制功能至关重要。
