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A role of β-catenin signaling loop on cell proliferation and differentiation of endometrial carcinomas : Implication for gene therapy

β-连环蛋白信号环路对子宫内膜癌细胞增殖和分化的作用：基因治疗的意义

基本信息

批准号：
17590315
负责人：
SAEGUSA Makoto
金额：
$ 2.37万
依托单位：
Kitasato University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590315/
关键词：
endometrial carcinoma beta-catenin TCF4 p300 p16 p53 p14 β-カテニン p16^<INK4A>pRb 子宮内膜癌細胞

项目摘要

Nuclear stabilization of β-catenin and its interaction with TCF/LEF factors are key events in transduction of the Wnt/ β-catenin signal pathway. We show here that β-catenin can directly induce transcription from the TCF4 promoter, the effect being enhanced by the p300 coactivator. In clinical cases, nuclear β-catenin accumulation was found to frequently overlap with TCF4 immunoreactivity in morules and surrounding glandular carcinoma lesions, showing a significant positive correlation (r=0.82, p<0.0001), in contrast to areas of squamous metaplasia (SqM) within Em Cas. The TCF4 promoter contains a single consensus TCF binding site that is critical for activation by β-catenin. The p300 coactivator appears sufficient to enhance β-catenin-dependent transcription, again with TCF4-dependence, indicating that a positive feedback loop of TCF4 expression mediated by β-catenin/p300 may be important for initial steps during trans-differentiation of Em Ca cells. In addition, transcriptional activation of p16^<INK4A> promoter by active form β-catenin occurred in a TCF4-independent manner. Moreover, cell proliferation was accompanied with phosphorylation of pRb and increased p16^<INK4A>, expression, while its inhibition by serum starvation caused decreased expression of total pRb but not p16^<INK4A>, resulting in high relative amounts of the latter, indicating that induction of p16^<INK4A> mediated by nuclear β-catenin and p21^<WAF1>, along with loss of pRb expression, may be important for initial steps during trans-differentiation of Em Ca cells.

β-连环蛋白的核稳定性及其与 TCF/LEF 因子的相互作用是 Wnt/β-连环蛋白信号通路转导中的关键事件。我们在此表明，β-连环蛋白可以直接诱导 TCF4 启动子的转录，p300 共激活子可增强该效果。在临床病例中，核β-连环蛋白的积累被发现经常与桑葚和周围腺癌病灶中的TCF4免疫反应性重叠，显示出显着的正相关性（r=0.82，p<0.0001），与Em Cas内的鳞状化生（SqM）区域相反。 TCF4 启动子包含一个共有的 TCF 结合位点，该位点对于 β-连环蛋白的激活至关重要。 p300 共激活因子似乎足以增强 β-连环蛋白依赖性转录，同样具有 TCF4 依赖性，表明由 β-连环蛋白/p300 介导的 TCF4 表达的正反馈环可能对于 Em Ca 细胞转分化过程中的初始步骤很重要。此外，活性形式β-连环蛋白对p16^<INK4A>启动子的转录激活以不依赖TCF4的方式发生。此外，细胞增殖伴随着 pRb 的磷酸化和 p16^<INK4A> 表达的增加，而血清饥饿对其的抑制导致总 pRb 的表达减少，但 p16^<INK4A> 的表达并未下降，导致后者的相对含量较高，表明 p16^<INK4A> 的诱导是由核 β-catenin 和 p21^<WAF1> 介导的，同时 p16^<INK4A> 的表达也随之丧失。 pRb 表达对于 Em Ca 细胞转分化过程中的初始步骤可能很重要。