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

β-连环蛋白的核稳定及其与Tcf/Lef因子的相互作用是Wnt/β-连环蛋白信号通路转导过程中的关键事件。我们在这里证明了β-连环蛋白可以直接诱导TCF4启动子的转录，这种作用被p300共激活因子增强。在临床病例中，核β-连环蛋白积聚经常与TCF4免疫反应重叠，呈显著正相关(r=0.82p&lt；0.0001)，而鳞状上皮化生区域(Sqm)则相反。TCF4启动子包含一个共同的Tcf结合位点，该结合位点对β-连环蛋白的激活至关重要。P300共激活子似乎足以增强β依赖的转录，同样依赖于TCF4，这表明由β-catenin/p300介导的TCF4表达的正反馈环在EmCa细胞反式分化的初始步骤中可能是重要的。此外，p16^-lt；ink4a&gt；启动子被活性形式β-catenin转录激活的方式不依赖于TCF4。此外，细胞增殖伴随着pRb的磷酸化和p16^lt；Ink4a；gt；的表达增加，而血清饥饿抑制导致总pRb的表达减少，但p16^lt；ink4a和gt；的相对含量较高，提示核β-catenin和p21^lt；waf1&gt；介导的p16^&lt；ink4a和gt；的诱导以及pRb的表达缺失可能是Em Ca细胞反式分化的初始步骤。

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.