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：
7940961
负责人：
JINGWU XIE
金额：
$ 27.3万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7940961
关键词：
Active Sites Address Affect Agonist Anchorage-Independent Growth Apoptosis Asbestos Basal Cell Basal cell carcinoma Binding Binding Proteins Biochemical Biological Breast Cancer Control Cellular biology Cilia Clinical Co-Immunoprecipitations Collaborations Complement component C1s Confocal Microscopy Data Drosophila genus Ectopic Expression Endosomes Environment Environmental Carcinogens Erinaceidae Event Fiber Figs - dietary Funding Gene Expression Gene Silencing Gene Targeting Goals Guanosine Triphosphate Phosphohydrolases Health Human Integral Membrane Protein Laboratories Length Ligands Link Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Molecular Monitor Mus Mutation Neoplasm Metastasis Nuclear Translocation Outcome Paper Pathway interactions Physiological Primary Neoplasm Process Prostate Proteins Publications Publishing RanBMP-90 Risk Factors Role Running Signal Transduction Skin Cancer Skin Neoplasms Specimen Tertiary Protein Structure Testing Transducers Vertebrates base cancer cell cancer type carcinogenesis cyclopamine exhaust gastrointestinal genetic regulatory protein human SMO protein human cancer mouse model in vivo innovation mouse model mutant novel overexpression prevent receptor research study response smoothened signaling pathway trafficking transcription factor tumor tumor growth tumor xenograft ultraviolet irradiation

项目摘要

DESCRIPTION (provided by applicant): Activation of the hedgehog (Hh) pathway, originally identified in fruit fly Drosophila, occurs in basal cell carcinomas (BCCs), gastrointestinal, prostate, breast and lung cancers. Environmental carcinogens are major risk factors for these cancers. The 7-transmembrane smoothened (SMO) is a key signal transducer of the Hh pathway, whose function is inhibited by the 12- transmembrane protein Patched (PTC) in the absence of Hh ligand. Hh signaling proceeds via binding of Hh ligand to its receptor, transcriptional factors. Gli transcription factors are responsible for Hh target gene expression. Little is known about signaling events from SMO to Gli transcriptional factors in vertebrates. For example, how SMO signaling is regulated, what are the molecular events that link SMO to downstream signaling, how does Hh signaling contribute to carcinogenesis? We have made significant progress to elucidate these issues. Most notably, we were the first group linking the Ran GTPase- binding protein, RanBPM, to the Hh signaling pathway. Our data indicate that RanBPM associates with SMO and regulates SMO signaling. Based on our data, we hypothesize that RanBPM is a novel component in the Hh pathway and is required for Hh signaling-mediated carcinogenesis. We will pursue three specific aims to test our central hypothesis and accomplish our objectives. First, we will determine the molecular basis of SMO-RanBPM interaction (Aim 1). Second, we will identify the mechanisms by which RanBPM facilitates SMO signaling (Aim 2). Third, determine the in vivo significance of RanBPM in Hh signaling-mediated carcinogenesis (Aim 3).Health relevance: Hedgehog signaling is frequently activated in human cancers, including most basal cell skin cancers and nearly a third of non-skin tumors. A large proportion of these tumors are caused by environmental carcinogens, such as UV irradiation, auto exhaust fumes and asbestos fibers. The emerging role of Hh signaling in different cancer types further emphasizes the relevance of studying this pathway to human health. Determining the mechanisms of signal transduction in this pathway, the long-term goal of this project, will have widespread clinical implications for cancer control. Identification of the novel SMO associated protein, RanBPM, provides a unique opportunity for us to dissect Hh signaling in human cancers.

描述（由申请人提供）：最初在果蝇果蝇中发现的刺猬蛋白（Hh）途径的激活发生在基底细胞癌（BCC）、胃肠道癌、前列腺癌、乳腺癌和肺癌中。环境致癌物是这些癌症的主要危险因素。 7 次跨膜平滑蛋白 (SMO) 是 Hh 通路的关键信号转导蛋白，在缺乏 Hh 配体的情况下，其功能会被 12 次跨膜蛋白 Patched (PTC) 抑制。 Hh 信号传导通过 Hh 配体与其受体（转录因子）的结合进行。 Gli 转录因子负责 Hh 靶基因的表达。关于脊椎动物中从 SMO 到 Gli 转录因子的信号转导事件知之甚少。例如，SMO信号传导是如何调节的，将SMO与下游信号传导联系起来的分子事件是什么，Hh信号传导如何促进致癌？我们在阐明这些问题方面取得了重大进展。最值得注意的是，我们是第一个将 Ran GTPase 结合蛋白 RanBPM 与 Hh 信号通路连接起来的团队。我们的数据表明 RanBPM 与 SMO 相关并调节 SMO 信号传导。根据我们的数据，我们假设 RanBPM 是 Hh 通路中的一个新成分，并且是 Hh 信号介导的致癌作用所必需的。我们将追求三个具体目标来检验我们的中心假设并实现我们的目标。首先，我们将确定 SMO-RanBPM 相互作用的分子基础（目标 1）。其次，我们将确定 RanBPM 促进 SMO 信号传输的机制（目标 2）。第三，确定 RanBPM 在 Hh 信号传导介导的致癌作用中的体内意义（目标 3）。健康相关性：Hedgehog 信号在人类癌症中频繁激活，包括大多数基底细胞皮肤癌和近三分之一的非皮肤肿瘤。这些肿瘤很大一部分是由环境致癌物引起的，例如紫外线照射、汽车尾气和石棉纤维。 Hh 信号在不同癌症类型中的新作用进一步强调了研究该通路与人类健康的相关性。该项目的长期目标是确定该途径中的信号转导机制，这将对癌症控制产生广泛的临床影响。新型 SMO 相关蛋白 RanBPM 的鉴定为我们剖析人类癌症中的 Hh 信号传导提供了独特的机会。