Molecular Basis of Hedgehog Signaling in Carcinogenesis

Hedgehog 信号传导在致癌过程中的分子基础

基本信息

批准号：
6620624
负责人：
JINGWU XIE
金额：
$ 26.52万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-01-29 至 2006-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6620624
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 transcription factor

项目摘要

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）Hedgehog 信令，最初描述在果蝇中，是脊椎动物发育中最重要的途径之一。该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。紫外线辐射是最多的基底细胞癌的重要危险因素。现在基底细胞癌据了解，与体细胞和种系基因突变有关声波刺猬信号通路。两个基因通常会发生突变、修补或平滑（SMO）。 SMO 信号活动受音速刺猬调节受体补丁。然而，大多数 sonic hedgehog 信号通路 SMO 的下游未知或知之甚少。我们已经证明了突变型 SMO 具有致癌性；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 是该通路的关键信号转导器，Gli1 是最终下游基底细胞癌形成的效应子。该通路的激活导致增加细胞增殖和肿瘤形成。因此抑制途径可有效减缓肿瘤形成。在这个提案中，我们将使用突变的SMO分子和下游分子Gli1作为生物用于分子鉴定、分离和功能解剖的探针协作调节基底细胞中的刺猬通路的成分癌。我们提出了三个具体目标： 1) 确定PDGFRalpha对于基底细胞癌的意义形成（目标 1）； 2) 确定PKA及其上游如何调节Glil磷酸化信号（目标 2）； 3) 确定SMO信号传导机制（目标3）。