Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
Adv Exp Med Biol. 2009;656:13-29. doi: 10.1007/978-1-4419-1145-2_2.
Mutational inactivation of the tumor suppressor gene APC (Adenomatous polyposis coli) is thought to be an initiating step in the progression of the vast majority ofcolorectal cancers. Attempts to understand APC function have revealed more than a dozen binding partners as well as several subcellular localizations including at cell-cell junctions, associated with microtubules at the leading edge of migrating cells, at the apical membrane, in the cytoplasm and in the nucleus. The present chapter focuses on APC localization and functions in the nucleus. APC contains two classical nuclear localization signals, with a third domain that can enhance nuclear import. Along with two sets of nuclear export signals, the nuclear localization signals enable the large APC protein to shuttle between the nucleus and cytoplasm. Nuclear APC can oppose beta-catenin-mediated transcription. This down-regulation of nuclear beta-catenin activity by APC most likely involves nuclear sequestration of beta-catenin from the transcription complex as well as interaction of APC with transcription corepressor CtBP. Additional nuclear binding partners for APC include transcription factor activator protein AP-2alpha, nuclear export factor Crm1, protein tyrosine phosphatase PTP-BL and perhaps DNA itself. Interaction of APC with polymerase beta and PCNA, suggests a role for APC in DNA repair. The observation that increases in the cytoplasmic distribution of APC correlate with colon cancer progression suggests that disruption of these nuclear functions of APC plays an important role in cancer progression. APC prevalence in the cytoplasm of quiescent cells points to a potential function for nuclear APC in control of cell proliferation. Clear definition of APC's nuclear function(s) will expand the possibilities for early colorectal cancer diagnostics and therapeutics targeted to APC.
肿瘤抑制基因 APC（结肠腺瘤性息肉病）的突变失活被认为是绝大多数结直肠癌进展的起始步骤。试图了解 APC 功能的研究揭示了十多个结合伴侣以及几个亚细胞定位，包括细胞-细胞连接处、与迁移细胞前缘微管相关、在顶膜上、在细胞质中和在核内。本章重点介绍 APC 在核内的定位和功能。APC 包含两个经典的核定位信号，还有一个可以增强核输入的第三结构域。与两组核输出信号一起，核定位信号使大的 APC 蛋白在核和细胞质之间穿梭。核 APC 可以对抗β-连环蛋白介导的转录。APC 对核β-连环蛋白活性的这种下调可能涉及核隔离β-连环蛋白从转录复合物以及 APC 与转录共抑制因子 CtBP 的相互作用。APC 的其他核结合伴侣包括转录因子激活蛋白 AP-2alpha、核输出因子 Crm1、蛋白酪氨酸磷酸酶 PTP-BL ，也许还有 DNA 本身。APC 与聚合酶β和 PCNA 的相互作用表明 APC 在 DNA 修复中的作用。APC 在细胞质中分布增加与结肠癌进展相关的观察表明，APC 的这些核功能的破坏在癌症进展中起着重要作用。APC 在静止细胞的细胞质中的存在指向了核 APC 在控制细胞增殖中的潜在功能。明确 APC 的核功能将扩大针对 APC 的早期结直肠癌诊断和治疗的可能性。
