Attenuated APC alleles produce functional protein from internal translation initiation

被引:26
作者
Goss, KH [1 ]
Trzepacz, C [1 ]
Tuohy, TMF [1 ]
Groden, J [1 ]
机构
[1] Univ Cincinnati, Coll Med, Howard Hughes Med Inst, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA
关键词
D O I
10.1073/pnas.112072199
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 beta-catenin, inhibits beta-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.
引用
收藏
页码:8161 / 8166
页数:6
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