Molecular Basis of Hedgehog Signaling in Carcinogenesis

Hedgehog 信号传导在致癌过程中的分子基础

• 批准号: 6997854
• 负责人: JINGWU XIE
• 金额: $ 25.9万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-29 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6997854
• 关键词: basal cell carcinoma; biological signal transduction; enzyme activity; gene induction /repression; genetically modified animals; growth factor receptors; laboratory mouse; membrane proteins; neoplasm /cancer genetics; oncoproteins; phosphoproteins; phosphorylation; platelet derived growth factor; protein kinase A; receptor expression; sonic hedgehog gene /protein; transcription factor

DESCRIPTION: (PROVIDED BY APPLICANT) Hedgehog signaling, originally described in Drosophila, is one of the most important pathways in vertebrate development. Disruption of this pathway leads to developmental disorders and cancers, particularly basal cell carcinoma. Basal cell carcinoma is the most common form of human cancer, affecting 750,000 Americans per year. UV radiation is the most important risk factor for basal cell carcinomas. Basal cell carcinoma is now understood to be associated with both somatic and germ line gene mutations in the sonic hedgehog signaling pathway. Two genes are commonly mutated, patched or smoothened (SMO). SMO signaling activity is regulated by the sonic hedgehog receptor-patched. However, most of the sonic hedgehog signaling pathway downstream of SMO is unknown or poorly understood. We have shown that the mutant SMO is oncogenic; it can transform cultured cells, and can lead to tumor formation when expressed in mouse skin. Our overall hypothesis is that SMO is the key signal transducer of the pathway, and Gli1 is the ultimate downstream effector for basal cell carcinoma formation. Activation of this pathway leads to increased cell proliferation and tumor formation. Therefore inhibiting the pathway could be effective in slowing tumor formation. In this proposal, we will use the mutant SMO molecule and the downstream molecule Gli1 as biological probes for the identification, isolation and functional dissection of molecular components that collaborate to regulate the hedgehog pathway in basal cell carcinomas. We proposed three specific aims: 1) To determine the significance of PDGFRalpha for basal cell carcinoma formation (Aim 1); 2) To determine how Glil phosphorylation is regulated by PKA and upstream signals (Aim 2); 3) To determine the mechanism of SMO signaling (Aim 3).

描述：（由申请人提供）刺猬信号，最初描述 在果蝇中，是脊椎动物发育中最重要的途径之一。 这种途径的破坏会导致发育障碍和癌症， 特别是基底细胞癌。基底细胞癌是最常见的形式 人类癌症，每年影响75万美国人。紫外辐射最多 基底细胞癌的重要危险因素。基底细胞癌现在 理解与体细胞系和种系基因突变有关 声音刺猬信号通路。两个基因通常是突变的，修补了 或平滑（SMO）。 SMO信号传导活动受声音刺猬的调节 受体攻击。但是，大多数声波刺猬信号通路 SMO的下游是未知或知之甚少的。我们已经证明了 突变的SMO是致癌的；它可以转化培养的细胞，并可能导致肿瘤 在小鼠皮肤中表达时形成。我们的总体假设是SMO是 途径的关键信号传感器，而Gli1是下游的最终 基底细胞癌的效应子。该途径的激活导致 增加细胞增殖和肿瘤形成。因此抑制 途径可以有效减慢肿瘤的形成。在这个建议中，我们 将使用突变体SMO分子和下游分子GLI1作为生物学 探测分子的鉴定，分离和功能解剖 合作调节基底细胞中的刺猬途径的组件 癌。我们提出了三个具体目标： 1）确定PDGFRALPHA对基底细胞癌的重要性 编队（目标1）； 2）确定如何通过PKA和上游调节神经胶质磷酸化 信号（AIM 2）； 3）确定SMO信号传导的机理（AIM 3）。