Tumorigenic fragments of APC cause dominant defects in directional cell migration in multiple model systems.
Tumorigenic fragments of APC cause dominant defects in directional cell migration in multiple model systems.
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DOI：
10.1242/dmm.008607
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发表时间：
2012-11
影响因子：
4.3
通讯作者：
Näthke IS
中科院分区：
文献类型：
--
作者：
Nelson SA;Li Z;Newton IP;Fraser D;Milne RE;Martin DM;Schiffmann D;Yang X;Dormann D;Weijer CJ;Appleton PL;Näthke IS
在大多数散发性和一些遗传性结直肠癌中发现了导致结肠腺瘤性息肉病（APC）肿瘤抑制蛋白的截短的N-末端片段表达的无义突变。这些突变可以通过从APC中消除β-连环蛋白结合位点而引起肿瘤发生，这导致β-连环蛋白的上调，从而导致致癌基因如MYC的诱导。在这里，我们表明，在三个不同的实验模型系统中，APC的N-末端片段（N-APC）的表达导致细胞运动的方向性丧失，但不依赖于β-连环蛋白调节的变化。我们开发了一个系统来培养和荧光标记活的肠道组织，以记录原位细胞的高分辨率三维延时电影。这揭示了正常肠道细胞迁移的意外复杂性，这是肠道上皮维持的关键过程，细胞在空间和时间上不连续地移动。野生型小鼠和APC杂合子（APCMin/+;多发性肠肿瘤模型）的肠组织的定量比较表明，癌前上皮中的细胞在沿沿着隐窝-绒毛轴移动时缺乏方向偏好。这种效应在不同的实验系统中重现：在发育中的鸡胚中，表达N-APC的中胚层细胞不能正常迁移;在缺乏内源性APC的变形网骨藻中，表达N-APC片段的细胞保持运动性，但细胞不能进行定向趋化;多细胞网骨藻蛞蝓聚集体同样不能进行趋光性。我们认为APC的N-末端片段代表了一种功能获得性突变，导致组织内的细胞无法响应相关的指导线索而定向迁移。与这一观点一致，APCMin/+肠的组织学正常组织中的隐窝中细胞过多，表明缺乏迁移可能导致癌前状态的细胞积聚。
Nonsense mutations that result in the expression of truncated, N-terminal, fragments of the adenomatous polyposis coli (APC) tumour suppressor protein are found in most sporadic and some hereditary colorectal cancers. These mutations can cause tumorigenesis by eliminating β-catenin-binding sites from APC, which leads to upregulation of β-catenin and thereby results in the induction of oncogenes such as MYC. Here we show that, in three distinct experimental model systems, expression of an N-terminal fragment of APC (N-APC) results in loss of directionality, but not speed, of cell motility independently of changes in β-catenin regulation. We developed a system to culture and fluorescently label live pieces of gut tissue to record high-resolution three-dimensional time-lapse movies of cells in situ. This revealed an unexpected complexity of normal gut cell migration, a key process in gut epithelial maintenance, with cells moving with spatial and temporal discontinuity. Quantitative comparison of gut tissue from wild-type mice and APC heterozygotes (APCMin/+; multiple intestinal neoplasia model) demonstrated that cells in precancerous epithelia lack directional preference when moving along the crypt-villus axis. This effect was reproduced in diverse experimental systems: in developing chicken embryos, mesoderm cells expressing N-APC failed to migrate normally; in amoeboid Dictyostelium, which lack endogenous APC, expressing an N-APC fragment maintained cell motility, but the cells failed to perform directional chemotaxis; and multicellular Dictyostelium slug aggregates similarly failed to perform phototaxis. We propose that N-terminal fragments of APC represent a gain-of-function mutation that causes cells within tissue to fail to migrate directionally in response to relevant guidance cues. Consistent with this idea, crypts in histologically normal tissues of APCMin/+ intestines are overpopulated with cells, suggesting that a lack of migration might cause cell accumulation in a precancerous state.
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影响因子：
4.8
作者：
Moseley, James B.;Bartolini, Francesca;Goode, Bruce L.
通讯作者：
Goode, Bruce L.
影响因子：
--
作者：
Nandan, Mandayam O;Yang, Vincent W
通讯作者：
Yang, Vincent W
同时与逐步APC丢失的不同表型后果。
影响因子：
8
作者：
Fischer, J. M.;Miller, A. J.;Shibata, D.;Liskay, R. M.
通讯作者：
Liskay, R. M.
影响因子：
3.7
作者：
Booth, C;O'Shea, JA;Potten, CS
通讯作者：
Potten, CS
影响因子：
2
作者：
Appleton, P. L.;Quyn, A. J.;Naethke, I.
通讯作者：
Naethke, I.