Expression of AIE-75 PDZ-domain protein induces G2/M cell cycle arrest in human colorectal adenocarcinoma SW480 cells
Expression of AIE-75 PDZ-domain protein induces G2/M cell cycle arrest in human colorectal adenocarcinoma SW480 cells
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DOI：
10.1016/j.canlet.2004.02.005
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发表时间：
2004-08-10
期刊：
影响因子：
9.7
通讯作者：
Moriuchi, T
中科院分区：
文献类型：
--
作者：
Hirai, A;Tada, M;Moriuchi, T
AIE-75是一种在自身免疫性肠病（AIE）血清中检测到的75-kDa自身抗原，也是一种结肠癌相关抗原，现在被指定为Usher综合征I型C遗传综合征性听力损失的基因病因。它通过PSD-95/Dlg/ZO-1 （PDZ）结构域与MCC（在结肠癌中突变）同源的新型推定肿瘤抑制因子MCC2结合。为了阐明AIE-75在结肠癌细胞中的功能作用，我们将AIE-75基因转染到不表达AIE-75的SW480结肠癌细胞中。AIE-75的表达对SW480细胞的体外生长有抑制作用，并与表达水平相关。这主要是由于与有丝分裂滑移相关的G(2)/M期细胞周期阻滞，导致超倍体巨核或多核细胞的出现。通过酵母双杂交系统筛选AIE-75 PDZ结构域结合蛋白，发现3个丝氨酸/苏氨酸磷酸酶催化亚基（pp2ac - α、pp2ac - β和PPP6C）可与AIE-75结合。由于已知PP2AC调节G2/M检查点，我们认为AIE-75与PP2AC相互作用并阻止细胞进入有丝分裂期。2004爱思唯尔爱尔兰有限公司版权所有。
AIE-75 has been known as a 75-kDa autoantigen detected in the serum of autoimmune enteropathy (AIE) and as a colon cancer-related antigen, and now designated as a gene causative of Usher syndrome type I C hereditary syndromic hearing loss. It binds to a novel putative tumor suppressor MCC2 that is homologous to MCC (mutated in colon cancer) through a PSD-95/Dlg/ZO-1 (PDZ) domain. To clarify the functional role in colon cancer cells, we transfected AIE-75 gene into SW480 colon cancer cells which do not express AIE-75. Expression of AIE-75 suppressed growth of SW480 cells in vitro in correlation with the expression levels. It was due mainly to G(2)/M phase cell cycle arrest associated with mitotic slippage, resulting in emergence of hyperploid giant-nucleated or multi-nucleated cells. Screening of proteins that bound to PDZ domains of AIE-75 by a yeast two hybrid system showed that three serine/threonine phosphatase catalytic subunits (PP2AC-alpha, PP2AC-beta, and PPP6C) could bind to AIE-75. Since PP2AC is known to regulate G2/M checkpoint, we suggest that AIE-75 interacts with PP2AC and prevent cells to transit mitotic phase. (C) 2004 Elsevier Ireland Ltd. All rights reserved.