Cross Regulation of Beta-catenin and Retinoid Signaling

描述（由申请人提供）：钙粘蛋白/连环蛋白/LEF的改变 粘附和信号系统在许多癌症中是常见的。LEF/TCF调节 基因在胚胎发生中也很重要。很明显，调节这种情况的因素 在发展的广阔领域， 致癌作用初步结果表明，视黄酸的直接作用 (RA)β-连环蛋白/LEF信号的调节。视黄酸受体 类维生素A受体α（RAR-α）而非类维生素A X受体α（RXR-α）相互作用 直接与β-连环蛋白在RA的存在下抑制 β-连环蛋白/TCF/LEF信号传导。β-连环蛋白也可以作为一种共激活剂， RAR调节基因。第一个目标是详细调查 β-连环蛋白-RAR相互作用的分子基础。具体来说，我们将 直接测试一个或多个的五个LXXLL基序中发现的作用， β-连环蛋白犰狳重复序列和激活功能-2（AF-2）结构域 RAR-α在目标2中，我们建议研究 β-连环蛋白/类维生素A交叉调节，并将研究常见的 辅激活子和阻遏子以及WNT- 1的。染色质免疫沉淀和 质谱将用于鉴定内源性的成分， β-连环蛋白/RAR复合物。新发现的致癌作用 β-连环蛋白/TCF信号传导和RA众所周知的癌症预防作用 明确确立了这些发现的临床意义，但未显示 这种相互作用在肿瘤形成的自然史中很重要， 胚胎发生我们的第三个目标是直接研究 发育和癌症中β-连环蛋白和类维生素A通路的交叉调节 模型系统为此，我们将首先测试RA对 非洲爪蟾中β-连环蛋白诱导的组织者基因表达和轴复制。 其次，我们将研究RA对β-连环蛋白调节的细胞周期蛋白D1的作用。 表达和结肠癌细胞的生长。在这两个模型中，我们将阐明 RA介导的AP-1抑制和 β-连环蛋白/TCF激活，RA介导的RAR应答基因刺激 以及辅激活子和辅抑制子的竞争。第三，我们将调查 RA对新转基因小鼠乳腺肿瘤发病率和生长的影响 其中β-连环蛋白在乳腺中过表达的动物模型。在 一般的工作提出测试的分子机制，和意义， β-连环蛋白/TCF类维生素A信号通路的交叉调节。

DESCRIPTION (provided by applicant): Alterations in the cadherin/catenin/LEF adhesion and signaling system are common in many cancers. LEF/TCF-regulated genes are also important in embryogenesis. Clearly, factors that regulate this pathway are likely to be important in the broad areas of development and carcinogenesis. Preliminary results demonstrate a direct role for retinoic acid (RA) in the regulation of beta-catenin/LEF signaling. Retinoic acid receptor alpha (RAR-alpha) but not retinoid X-receptor alpha (RXR-alpha) interacts directly with beta-catenin in the presence of RA to inhibit beta-catenin/TCF/LEF signaling. Beta-catenin can also act as a co-activator for RAR-regulated genes. The first aim is directed at a detailed investigation of the molecular basis of beta-catenin-RAR interactions. Specifically we will directly test the role of one or more of the five LXXLL motifs found in the beta-catenin armadillo repeats and the activation function-2 (AF-2) domain of RAR-alpha. In aim 2 we propose to study the molecular mechanisms of beta-catenin/retinoid cross regulation and will investigate the role of common coactivators and repressors, and of wnt- 1. Chromatin immunoprecipitation and mass spectroscopy will be used to identify components of the endogenous beta-catenin/RAR complexes. The newly discovered oncogenic effects of beta-catenin/TCF signaling and the well known cancer preventive actions of RA clearly establish the clinical significance of these findings but do not show that the interaction is important in the natural history of neoplasia or in embryogenesis. Our third aim is to directly investigate the significance of beta-catenin and retinoid pathway cross-regulation in developmental and cancer model systems. To do this we will first test the effects of RA on beta-catenin-induced organizer gene expression and axis duplication in Xenopus. Secondly we will investigate the role of RA on beta-catenin regulated cyclin D1 expression and growth of colon cancer cells. In both models we will elucidate the relative contribution of RA-mediated inhibition of AP-1 and beta-catenin/TCF activation, RA mediated stimulation of RAR-responsive genes and co-activator and co-repressor competition. Thirdly, we will investigate the effects of RA on the incidence and growth of breast tumors in a new transgenic animal model in which beta-catenin is over expressed in the mammary gland. In general the work proposed tests the molecular mechanisms, and significance of, cross regulation of beta-catenin/TCF retinoid signaling pathways.