Adenomatous polyposis coli (Apc) tumor suppressor gene as a multifunctional gene
Adenomatous polyposis coli (Apc) tumor suppressor gene as a multifunctional gene
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DOI：
10.1111/j.1447-073x.2005.00106.x
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发表时间：
2005-09-01
影响因子：
1.2
通讯作者：
Iizuka-Kogo, Akiko
中科院分区：
文献类型：
--
作者：
Senda, Takao;Shimomura, Atsushi;Iizuka-Kogo, Akiko
家族性腺瘤性息肉病和散发性结直肠肿瘤中的腺瘤性结肠息肉病（Apc）基因发生突变。Apc基因产物（APC）基本上是一种细胞质蛋白，阻断细胞周期进程，在发育中起着至关重要的作用。APC与β-连环蛋白、轴蛋白和糖原合成酶激酶3 β结合以形成大的蛋白质复合物，其中β-连环蛋白被磷酸化并分解，导致Wnt信号传导途径的负调节。大肠癌中大多数突变的Apc基因缺乏β-连环蛋白结合区，无法抑制Wnt信号传导，导致肿瘤细胞过度增殖。APC分子中含有核定位信号，也可定位于细胞核。核APC将过量的β-连环蛋白输出到细胞质。APC通过其C-末端与突触后致密盘大悬带结合。这些蛋白质在上皮细胞形态发生、脑发育和神经元功能中起重要作用。此外，APC通过与微管和APC刺激的鸟嘌呤核苷酸交换因子的结合参与细胞运动。APC和DLG的共定位依赖于微管。Apc基因在胚胎和出生后发育的大脑中高度表达。最近，我们发现APC通过促进PSD-95和这些受体在突触后的聚集而对α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的活性是必需的。此外，APC存在于星形胶质细胞中，尽管其在星形胶质细胞中的作用尚不清楚。
The adenomatous polyposis coli (Apc) gene is mutated in familial adenomatous polyposis and in sporadic colorectal tumors. The Apc gene product (APC), basically a cytoplasmic protein, blocks cell cycle progression and plays crucial roles in development. The APC binds to beta-catenin, axin and glycogen synthase kinase 3 beta to form a large protein complex, in which beta-catenin is phosphorylated and broken down, resulting in negative regulation of the Wnt signaling pathway. Most of the mutated Apc genes in colorectal tumors lack beta-catenin-binding regions and fail to inhibit Wnt signaling, leading to overproliferation of tumor cells. The APC, having some nuclear localizing signals in its molecule, can also be localized in the nucleus. The nuclear APC exports excess beta-catenin to the cytoplasm. Through its C-terminus, APC binds to post-synaptic density discs large zonula. occludens domain-containing proteins, such as discs large (DLG) and post-synaptic density (PSD)-95, and may play important roles in epithelial morphogenesis, brain development and neuronal functions. In addition, APC is involved in cell motility through its association with microtubules and APC-stimulated guanine nucleotide exchange factor. Colocalization of APC and DLG is dependent on microtubules. The Apc gene is highly expressed in the embryonic and postnatal developing brain. Recently, we found that APC is required for the activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by facilitating the clustering of PSD-95 and these receptors at the postsynapse. In addition, APC is present in astrocytes, although its role in astrocytes is, as yet, unknown.