MIM regulates Shh target gene expression in tumors

MIM 调节肿瘤中 Shh 靶基因表达

基本信息

批准号：
7750671
负责人：
Scott Atwood
金额：
$ 4.72万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7750671
关键词：
Actins Bardet-Biedl Syndrome Basal cell carcinoma Binding Binding Sites Biochemical Biochemistry Biological Biological Assay Breast Cells Chemosensitization Cilia Cytokinesis Cytoskeleton Data Defect Dermis Development Disease Epidermis Epithelial Erinaceidae Event Family Fellowship Funding Gene Expression Genetic Genetic Techniques Genetic Transcription Goals Growth Guanosine Triphosphate Phosphohydrolases Hair Human Life Liver diseases Lung Malignant Neoplasms Mammalian Cell Mediating Membrane Membrane Protein Traffic Microtubules Natural regeneration Neoplasm Metastasis Oncogenes Oncogenic Organ Organelles Outcome Output Pancreas Pathway interactions Polycystic Kidney Diseases Process Prostate Recruitment Activity Regulation Retinal Degeneration Role Signal Transduction Stem cells Tertiary Protein Structure Tissue Model Tumor Suppressor Proteins Vesicle Work base carcinogenesis cell type cellular imaging cilium biogenesis gene induction genetic analysis human SMO protein human tissue insight kinetosome malignant breast neoplasm medulloblastoma member migration novel prevent rab GTP-Binding Proteins smoothened signaling pathway transcription factor tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand how unregulated epithelial proliferation and invasion leads to carcinogenesis. Sonic hedgehog (Shh) signaling controls the proliferation and migration of progenitor cells of many organs, and uncontrolled Shh target gene induction promotes growth and invasion of 25% of human cancers including lung, breast, prostate, pancreatic, as well as medulloblastoma and basal cell carcinoma. While the Gli family of transcription factors mediates the transcriptional effects of Shh, the mechanism for controlling Gli transcriptional output and Shh-dependent migration and invasion during normal and oncogenic contexts remain poorly understood. Shh signaling components including Suppressor of fused (Sufu) and Smoothened have been shown to concentrate at the primary cilia, a dynamic microtubule-based signaling organelle. Primary cilia are found on most mammalian cells and Shh signaling components concentrate at the cilia in order to regulate Gli3 cleavage and Gli1/2 activation. Loss of cilia leads to defects in Shh signaling and a variety of developmental defects and disorders that range from certain types of retinal degeneration and hair loss to polycystic kidney/liver disease and Bardet-Biedl syndrome. We have identified a novel Shh pathway member, Missing in Metastasis (MIM), a BAR-domain protein that regulates membrane dynamics and whose levels are altered in a variety of epithelial cancers and negatively correlates with outcome in breast cancer. So far, we have established that MIM is required for Shh target gene induction in many cell types and cooperates with the tumor suppressor Sufu, a major negative regulator of Shh signaling, and the Gli oncogene to recapitulate Shh-mediated epithelial proliferation and invasion. In addition, MIM is required for primary cilia formation. Our working hypothesis is that MIM functions to regulate Shh target gene expression in tumors by promoting primary cilia formation and antagonizing Sufu. This proposal seeks to utilize a combination of biochemical, cell biological, and genetic techniques to: 1) Determine the mechanism by which MIM regulates membrane dynamics during ciliogenesis and 2) Determine the mechanism of MIM-dependent potentiation of Sonic hedgehog signaling at the primary cilium. Funding this fellowship will allow us to gain insight into Shh-mediated tumor growth and invasion and Shh signaling in cilia-related disorders.

描述（由申请人提供）：该项目的长期目标是了解不受调节的上皮增殖和侵袭如何导致癌变。 Sonic hidehog (Shh) 信号控制许多器官的祖细胞的增殖和迁移，不受控制的 Shh 靶基因诱导可促进 25% 的人类癌症的生长和侵袭，包括肺癌、乳腺癌、前列腺癌、胰腺癌以及髓母细胞瘤和基底细胞癌癌。虽然转录因子 Gli 家族介导 Shh 的转录作用，但在正常和致癌背景下控制 Gli 转录输出和 Shh 依赖性迁移和入侵的机制仍知之甚少。 Shh 信号传导成分，包括 Suppressor of fused (Sufu) 和 Smoothened，已被证明集中在初级纤毛，这是一种基于动态微管的信号细胞器。大多数哺乳动物细胞上都有初级纤毛，Shh 信号传导成分集中在纤毛上，以调节 Gli3 裂解和 Gli1/2 激活。纤毛缺失会导致 Shh 信号传导缺陷以及各种发育缺陷和疾病，包括某些类型的视网膜变性和脱发、多囊肾/肝病和 Bardet-Biedl 综合征。我们发现了一种新的 Shh 通路成员，即转移缺失 (MIM)，这是一种调节膜动力学的 BAR 结构域蛋白，其水平在多种上皮癌中发生改变，并与乳腺癌的预后呈负相关。到目前为止，我们已经确定MIM是许多细胞类型中Shh靶基因诱导所必需的，并与肿瘤抑制因子Sufu（Shh信号传导的主要负调节因子）和Gli癌基因配合以重现Shh介导的上皮增殖和侵袭。此外，初级纤毛的形成需要 MIM。我们的工作假设是，MIM 通过促进初级纤毛形成和拮抗 Sufu 来调节肿瘤中的 Shh 靶基因表达。该提案旨在综合利用生化、细胞生物学和遗传技术来：1) 确定 MIM 在纤毛发生过程中调节膜动力学的机制，以及 2) 确定初级纤毛中 Sonic Hedgehog 信号传导的 MIM 依赖性增强机制。资助这项研究金将使我们能够深入了解Shh介导的肿瘤生长和侵袭以及纤毛相关疾病中的Shh信号传导。