A common role for various human truncated adenomatous polyposis coli isoforms in the control of beta-catenin activity and cell proliferation.
A common role for various human truncated adenomatous polyposis coli isoforms in the control of beta-catenin activity and cell proliferation.
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各种人类截短的腺瘤性息肉病大肠杆菌同工型在控制β-蛋白 - - - - - - 钙蛋白活性和细胞增殖中）的共同作用。
DOI：
10.1371/journal.pone.0034479
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Schneikert J
中科院分区：
文献类型：
--
作者：
Chandra SH;Wacker I;Appelt UK;Behrens J;Schneikert J
肿瘤抑制基因腺瘤性结肠息肉病（APC）在大多数结直肠癌病例中发生突变，导致合成截短的APC产物和β-连环蛋白的稳定化。截短的APC几乎总是保留在肿瘤细胞中，这表明它具有重要的功能。在这里，RNA干扰已被用于下调截短的APC在几个结直肠癌细胞系表达截短的APC的不同长度，从而进行分析，涵盖了大部分的突变簇区域（MCR）。已经研究了对体外增殖、体内肿瘤形成以及β-连环蛋白的水平和转录活性的影响。截短的APC的下调导致在6个细胞系中的6个细胞系中体外肿瘤细胞群扩增的抑制和体内肿瘤生长的抑制，如在这些细胞系之一HT 29中所分析的。这提供了解释截短的APC在结直肠肿瘤中保留的一般规则，并将其定义为治疗干预的合适靶点。事实上，我们也表明，它是可能的设计一个shRNA的目标是一个特定的截短亚型的APC，而不改变野生型APC的表达。在6个细胞系中的5个中，截短的APC的下调伴随着β-连环蛋白的转录活性的上调。令人惊讶的是，在大多数情况下（5个中的4个），增加的信号传导与β-连环蛋白水平的上调相关，表明截短的APC仍然可以通过控制β-连环蛋白的水平来调节wnt信号传导。即使当截短的APC缺乏参与靶向β-连环蛋白以进行蛋白酶体降解的β-连环蛋白抑制结构域（CiD）时，这种控制也可以发生。因此，截短的APC是结肠直肠癌细胞的重要组成部分，可能通过将β-连环蛋白信号传导调节到“恰到好处”的水平来实现细胞增殖。
The tumour suppressor gene adenomatous polyposis coli (APC) is mutated in most colorectal cancer cases, leading to the synthesis of truncated APC products and the stabilization of β-catenin. Truncated APC is almost always retained in tumour cells, suggesting that it serves an essential function. Here, RNA interference has been used to down-regulate truncated APC in several colorectal cancer cell lines expressing truncated APCs of different lengths, thereby performing an analysis covering most of the mutation cluster region (MCR). The consequences on proliferation in vitro, tumour formation in vivo and the level and transcriptional activity of β-catenin have been investigated. Down-regulation of truncated APC results in an inhibition of tumour cell population expansion in vitro in 6 cell lines out of 6 and inhibition of tumour outgrowth in vivo as analysed in one of these cell lines, HT29. This provides a general rule explaining the retention of truncated APC in colorectal tumours and defines it as a suitable target for therapeutic intervention. Actually, we also show that it is possible to design a shRNA that targets a specific truncated isoform of APC without altering the expression of wild-type APC. Down-regulation of truncated APC is accompanied by an up-regulation of the transcriptional activity of β-catenin in 5 out of 6 cell lines. Surprisingly, the increased signalling is associated in most cases (4 out of 5) with an up-regulation of β-catenin levels, indicating that truncated APC can still modulate wnt signalling through controlling the level of β-catenin. This control can happen even when truncated APC lacks the β-catenin inhibiting domain (CiD) involved in targeting β-catenin for proteasomal degradation. Thus, truncated APC is an essential component of colorectal cancer cells, required for cell proliferation, possibly by adjusting β-catenin signalling to the “just right” level.
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影响因子：
64.5
作者：
GRODEN, J;THLIVERIS, A;WHITE, R
通讯作者：
WHITE, R
影响因子：
24.5
作者：
Lewis A;Segditsas S;Deheragoda M;Pollard P;Jeffery R;Nye E;Lockstone H;Davis H;Clark S;Stamp G;Poulsom R;Wright N;Tomlinson I
通讯作者：
Tomlinson I
影响因子：
5.3
作者：
Lustig, B;Jerchow, B;Behrens, J
通讯作者：
Behrens, J
影响因子：
3.5
作者：
Albuquerque, C;Breukel, C;Smits, R
通讯作者：
Smits, R
DOI：
10.1073/pnas.91.19.8969
发表时间：
1994-09-13
影响因子：
11.1
作者：
FODDE, R;EDELMANN, W;KUCHERLAPATI, R
通讯作者：
KUCHERLAPATI, R