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：
7496604
负责人：
JINGWU XIE
金额：
$ 26.77万
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 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7496604
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 Glutathione S-Transferase 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 Numbers Outcome Paper Pathway interactions Physiological Primary Neoplasm Process Prostate Protein Overexpression 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 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）：最初在果蝇中鉴定出的刺猬（HH）途径的激活发生在基底细胞癌（BCC），胃肠道，前列腺，前列腺，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跨膜平滑（SMO）是HH途径的关键信号传感器，在没有HH配体的情况下，其功能被12-跨膜蛋白（PTC）抑制。 HH信号通过HH配体与其受体（转录因子）结合而进行。 GLI转录因子负责HH靶基因表达。关于脊椎动物中从SMO到GLI转录因子的信号事件知之甚少。例如，如何调节SMO信号，将SMO与下游信号联系起来的分子事件是什么，HH信号传导如何促进致癌？我们已经取得了重大进展来阐明这些问题。最值得注意的是，我们是将RAN GTPase结合蛋白RANBPM与HH信号通路联系起来的第一组。我们的数据表明RANBPM与SMO相关并调节SMO信号。根据我们的数据，我们假设RANBPM是HH途径中的一种新成分，是HH信号介导的癌变所必需的。我们将追求三个特定的目标，以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（AIM 1）。其次，我们将确定RANBPM促进SMO信号传导的机制（AIM 2）。第三，确定RANBPM在HH信号介导的癌变中的体内显着性（AIM 3）。健康相关性：刺猬信号传导经常在人类癌症中激活，包括大多数基底细胞皮肤癌和近三分之一的非皮肤肿瘤。这些肿瘤中很大一部分是由环境致癌物（例如紫外线辐射，自动排气烟雾和石棉纤维）引起的。 HH信号在不同癌症类型中的新兴作用进一步强调了研究这种对人类健康途径的相关性。确定该途径中信号转导的机制（该项目的长期目标）将对癌症控制具有广泛的临床意义。新型SMO相关蛋白RANBPM的识别为我们为剖析人类癌症的HH信号传导提供了独特的机会。