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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-catenin的核稳定化及其与TCF/LEF因子的相互作用是Wnt/ β-catenin信号转导途径中的关键事件。我们发现β-catenin可以直接诱导TCF 4启动子的转录，p300辅激活因子可以增强这种作用。在临床病例中，与Em Cas内的鳞状化生（SqM）区域相反，发现细胞核β-连环蛋白积聚经常与桑椹胚和周围腺癌病变中的TCF 4免疫反应性重叠，显示出显著的正相关性（r=0.82，p<0.0001）。TCF 4启动子包含一个单一的共有TCF结合位点，该位点对于β-连环蛋白的激活至关重要。p300辅激活因子似乎足以增强β-连环蛋白依赖性转录，再次具有TCF 4依赖性，表明由β-连环蛋白/p300介导的TCF 4表达的正反馈环可能对Em Ca细胞转分化过程中的初始步骤很重要。此外，<INK4A>活性形式β-catenin对p16^启动子的转录激活以TCF 4非依赖性方式发生。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引起总pRb表达的降低，但不引起p16^的降低<INK4A>，导致后者的相对量较高，这表明<INK4A>由核β-连环蛋白和p21^介导<WAF1>的p16^的诱导，沿着pRb表达的丧失，可能对于Em Ca细胞转分化过程中的初始步骤是重要的。