Cross Regulation of Beta-catenin and Retinoid Signaling

描述(申请人提供)：钙粘附素/连环蛋白/LEF的改变 黏附和信号系统在许多癌症中都很常见。LEF/TCF调节 基因在胚胎发育中也很重要。显然，规范这一点的因素 途径可能在发展和发展的广泛领域中很重要 致癌。初步结果显示维甲酸具有直接作用。 (Ra)在β-连环蛋白/Lef信号的调节中。维甲酸受体 α(RAR-α)与维甲酸X受体α(RXR-α)相互作用 直接用β-连环蛋白在RA存在下抑制 β-连环蛋白/TCF/Lef信号转导。β-连环蛋白也可以作为一种共同激活剂 受RAR调节的基因。第一个目的是详细调查 β-连环蛋白-RAR相互作用的分子基础。具体来说，我们将 直接测试五个LxxLL主题中的一个或多个的作用 β-连环蛋白重复序列及其激活功能-2(AF-2)结构域 RAR-阿尔法。在目标2中，我们建议研究其分子机制。 β-连环蛋白/维甲酸的交叉调节，并将调查共同的作用 共激活物和抑制物，以及WNT-1。染色质免疫沉淀和 将使用质谱学来鉴定内源的成分 β-连环蛋白/RAR复合体。新发现的致癌作用 β-连环蛋白/TCF信号转导与RA的防癌作用 清楚地确立了这些发现的临床意义，但没有显示 这种相互作用在肿瘤的自然病程中或在 胚胎发生。我们的第三个目标是直接调查 β-连环蛋白和维甲酸途径在发育和癌症中的交叉调节 模型系统。要做到这一点，我们将首先测试RA对 β-连环蛋白诱导非洲爪哇组织者基因表达和轴复制。 其次，我们将研究RA在β-连环蛋白调节的细胞周期蛋白D1中的作用 结肠癌细胞的表达和生长。在这两个模型中，我们都将阐明 RA介导的AP-1和AP-1抑制作用的相对贡献 β-连环蛋白/TCF激活，视黄酸介导的RAR反应基因的刺激 以及共同激活者和共同抑制者的竞争。第三，我们将调查 维甲酸对新型转基因乳腺肿瘤发生和生长的影响 β-连环蛋白在乳腺过度表达的动物模型。在……里面 一般提出的工作测试分子机制，和意义， β-连环蛋白/视黄酸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.