Attenuated APC alleles produce functional protein from internal translation initiation

Some truncating mutations of the APC tumor suppressor gene are associated with an attenuated phenotype of familial adenomatous polyposis coli (AAPC). This work demonstrates that APC alleles with 5′ mutations produce APC protein that down-regulates β-catenin, inhibits β-catenin/T cell factor-mediated transactivation, and induces cell-cycle arrest. Transfection studies demonstrate that cap-independent translation is initiated internally at an AUG at codon 184 of APC. Furthermore, APC coding sequence between AAPC mutations and AUG 184 permits internal ribosome entry in a bicistronic vector. These data suggest that AAPC alleles in vivo may produce functional APC by internal initiation and establish a functional correlation between 5′ APC mutations and their associated clinical phenotype.

APC肿瘤抑制基因（APC tumor suppressor gene）的部分截短突变与弱化型家族性腺瘤性息肉病（attenuated familial adenomatous polyposis coli, AAPC）的表型密切相关。本研究证实，携带5'端突变的APC等位基因所编码的APC蛋白可下调β-连环蛋白（β-catenin）、抑制β-连环蛋白/T细胞因子（T cell factor）介导的反式激活过程，并诱导细胞周期阻滞。转染实验结果显示，帽非依赖翻译（cap-independent translation）可在APC基因第184位密码子对应的AUG起始位点内部启动。进一步研究发现，位于AAPC突变区域与第184位AUG之间的APC编码序列，可在双顺反子载体（bicistronic vector）中介导内部核糖体进入。上述数据表明，体内的AAPC等位基因可通过内部起始翻译途径产生功能性APC蛋白，并建立了APC 5'端突变与其对应的临床表型之间的功能相关性。