Neufeld K L, Zhang F, Cullen B R, White R L
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City 84112, USA.
EMBO Rep. 2000 Dec;1(6):519-23. doi: 10.1093/embo-reports/kvd117.
Mutational inactivation of adenomatous polyposis coli (APC) initiates most colon carcinomas. APC functions include targeting cytoplasmic beta-catenin, a Wnt pathway mediator, for proteolysis. Although APC shuttles between cytoplasm and nucleus, the role of nuclear APC protein, particularly with respect to nuclear beta-catenin levels and activity, remains unclear. Here, we demonstrate that APC lacking functional nuclear localization signals (NLSs) or nuclear export signals (NESs) does not effectively downregulate nuclear beta-catenin levels; neither does wild-type APC when nuclear export is blocked. While APC bearing mutated NLSs could not downregulate beta-catenin-mediated transcriptional activation, APC lacking NESs remained active. Consistent with the hypothesis that nuclear APC lacking NESs can inhibit beta-catenin function by sequestration, we show that endogenous APC and beta-catenin proteins interact within the nucleus. These data demonstrate that nuclear APC binding to beta-catenin, and then inducing its nuclear export, plays a critical role in the control of nuclear beta-catenin levels and activity.
腺瘤性息肉病大肠杆菌（APC）的突变失活引发了大多数结肠癌。APC的功能包括将细胞质中的β-连环蛋白（一种Wnt信号通路介质）靶向进行蛋白水解。尽管APC在细胞质和细胞核之间穿梭，但核APC蛋白的作用，尤其是关于核β-连环蛋白水平和活性方面，仍不清楚。在此，我们证明缺乏功能性核定位信号（NLSs）或核输出信号（NESs）的APC不能有效下调核β-连环蛋白水平；当核输出被阻断时，野生型APC也不能。虽然带有突变NLSs的APC不能下调β-连环蛋白介导的转录激活，但缺乏NESs的APC仍具有活性。与缺乏NESs的核APC可通过隔离抑制β-连环蛋白功能的假设一致，我们表明内源性APC和β-连环蛋白蛋白在细胞核内相互作用。这些数据表明，核APC与β-连环蛋白结合，然后诱导其核输出，在控制核β-连环蛋白水平和活性中起关键作用。
