β-catenin simultaneously induces activation of the p53-p21WAF1 pathway and overexpression of cyclin D1 during squamous differentiation of endometrial carcinoma cells
β-catenin simultaneously induces activation of the p53-p21WAF1 pathway and overexpression of cyclin D1 during squamous differentiation of endometrial carcinoma cells
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DOI：
10.1016/s0002-9440(10)63732-7
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发表时间：
2004-05-01
影响因子：
6
通讯作者：
Okayasu, I
中科院分区：
文献类型：
--
作者：
Saegusa, M;Hashimura, M;Okayasu, I
在不同的肿瘤中，β-连环蛋白作为转录因子上调的功能后果是复杂的。为阐明子宫内膜癌(Em Ca)鳞状细胞分化(SQD)过程中的作用，我们研究了80例具有SQD区的Fin Ca组织中β-连环素、细胞周期蛋白D1、P53、p21WAF1和PML的表达，并与Ki-67抗原阳性确定的细胞增殖情况进行了比较。β-连环蛋白-T细胞的影响。Fin Ca细胞也检测了因子(TCF)介导的转录。在临床病例中，β-连环素在SQD区的核聚集更为频繁，与细胞周期蛋白D1、P53、p21WAF1的表达呈正相关，与Ki-67、PML免疫反应呈负相关。细胞核β-连环蛋白、细胞周期蛋白D1、p53和p21WAF1在SQD中的表达与癌旁病变显著相关。突变的β-连环蛋白稳定表达或受四环素调控的Ishikawa细胞株表现出细胞周期蛋白D1、p14ARF、p53和p21WAF1的表达水平增加，但不表达PML，并激活了用TOP/FOP构建的β-连环蛋白-TCF4介导的转录。细胞形态呈衰老样，而不是鳞片状。此外，过表达的β-连环蛋白可以激活p14ARF和细胞周期蛋白D1启动子的转录，并依赖于TCF4。这些结果表明，在Em Cas中，核6-catenin可以同时诱导p53-p21WAF1通路的激活和细胞周期蛋白D1的过度表达，从而抑制细胞增殖或诱导细胞衰老。然而，仅有β-连环蛋白的过度表达并不足以在Em Ca细胞中形成鳞状表型，这表明核聚集是反式分化的初始信号。
The functional consequences of up-regulation of beta-catenin as a transcription factor are complex in different tumors. To clarify roles during squamous; differentiation (SqD) of endometrial carcinoma (Em Ca) cells, we investigated expression of beta-catenin, as well as cyclin D1, P53, p21WAF1, and PML (promyelocytic leukemia) in 80 cases of Fin Ca with SqD areas, in comparison with cell proliferation determined with reference to Ki-67 antigen positivity. The impact of beta-catenin-T-cell. factor (TCF)-mediated transcription was also examined using Fin Ca cells. In clinical cases, nuclear beta-catenin accumulation was more frequent in SqD areas, being positively linked with expression of cyclin D1, P53, and p21WAF1, and inversely with Ki-67 and PML immunoreactivity. Significant correlations of nuclear beta-catenin, cyclin D1, P53, and p21WAF1 were noted between SqD and the surrounding carcinoma lesions. The Ishikawa cell line, with stable or tetracycline-regulated expression of mutant beta-catenin, showed an increase in expression levels of cyclin D1, p14ARF, p53, and p21WAF1 but not PML, and activation of beta-catenin-TCF4-mediated transcription determined with TOP/FOP constructs. The cell morphology was senescence-like rather than squamoid in appearance. Moreover, over-expressed beta-catenin could activate transcription from p14ARF and cyclin D1 promoters, in a TCF4-dependent manner. These findings indicate that in Em Cas, nuclear 6-catenin can simultaneously induce activation of the p53-p21WAF1 pathway and overexpression of cyclin D1, leading to suppression of cell proliferation or induction of cell senescence. However, overexpression of beta-catenin alone is not sufficient for development of a squamoid phenotype in Em Ca cells, suggesting that nuclear accumulation is an initial signal for trans-differentiation.