Regulation of beta1 integrin glycosylation by ras

ras 对 β1 整合素糖基化的调节

基本信息

批准号：
8078107
负责人：
Susan L Bellis
金额：
$ 23.75万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2002-01-09 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8078107
关键词：
Address Adhesions Anchorage-Independent Growth Antibodies Apoptosis Attenuated Behavior Binding Biological Assay CD29 Antigen Cecum Cell Adhesion Cell Communication Cell Line Cell Survival Cell-Cell Adhesion Cells Collagen Colon Colon Carcinoma Colonic Neoplasms Complement Complex Engineering Epithelial Cells Exhibits Extracellular Matrix Fluorescence Resonance Energy Transfer Galectin 3 Goals Human In Vitro Individual Injection of therapeutic agent Integrin Binding Integrin alpha Chains Integrins Laboratories Lectin Ligand Binding Link Liver Malignant Neoplasms Maps Mediating Molecular Molecular Conformation Monitor N-Glycosylation Site Neoplasm Metastasis Normal tissue morphology Nude Mice Oncogenic Physiological Play Polysaccharides Primary Neoplasm Principal Investigator Process Publishing Regulation Research Personnel Role ST6Gal I Sialic Acids Sialyltransferases Signal Transduction Simulate Site Structure Subcutaneous Injections Talin Transferase Tumor Cell Line Up-Regulation Variant Work adhesion receptor angiogenesis cell behavior cell motility effective therapy enzyme substrate extracellular glycosylation implantation matrigel migration molecular mass mortality mutant neoplastic cell novel programs ras Oncogene receptor response sialylation sugar tumor tumor growth tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Much of the mortality associated with cancer results from uncontrolled metastasis of the primary tumor. Metastasis is a poorly-understood process, for which there are few effective treatments. It is well-accepted that tumor cell association with the extracellular matrix comprises an important factor in metastasis, and in turn, this interaction is regulated by cell adhesion receptors such as integrins. Work from our laboratory has identified a novel mechanism for regulation of the beta l subfamily of integrin receptors. In particular, we have found that beta l integrin function is modulated by the acquisition of alpha 2-6 sialic acids, a sugar structure added by ST6Gal I, a sialyl transferase which has long been implicated in the progression/metastasis of colon carcinoma. Our work suggests that ST6Gal I, and accordingly, integrin alpha 2-6 sialylation, are upregulated in tumor cell lines that have oncogenic ras, as well as in human colon tumors. In vitro studies further suggest that integrin sialylation has a marked on the adhesion, migration and invasiveness of colon tumor cells. To better understand the contribution of sialylation to integrin structure/function, as well as the potential role of integrin sialylation in tumor cell metastasis, we have proposed the following aims: Specific Aim 1: Influence of site-specific glycosylation on integrin conformation and function. As part of this aim, we will characterize the conformation and function of integrins that have each of the individual N- glycosylation sites ablated. Specific Aim 2: Effects of integrin sialylation on galectin-3-regulated cell behaviors. We will examine the role of integrin sialylation in regulating gal-3 - induced cellular responses including adhesion, migration, invasion and apoptosis. Specific Aim 3: Modulation of metastasis-related cell behaviors by ras-directed differential sialylation. These studies aim to determine whether integrin sialylation serves as a downstream effector of ras in mediating behaviors such as anchorage-independent growth and invasion. Specific Aim 4: Role of integrin sialylation in promoting tumor growth and/or metastasis in nude mice. We will monitor tumorigenesis and metastasis of cells with variant levels of integrin sialylation.

描述（由申请人提供）：与癌症相关的许多死亡率是由原发性肿瘤不受控制的转移而导致的。转移是一个不当理解的过程，很少有有效的治疗方法。众所周知，肿瘤细胞与细胞外基质的缔合是转移中的重要因素，而这种相互作用又受细胞粘附受体（如整联蛋白）的调节。我们实验室的工作已经确定了调节整联蛋白受体亚科的新机制。特别是，我们发现βL整联蛋白功能是通过获得α2-6唾液酸的获得调节的，α2-6唾液酸是由ST6GAL I添加的糖结构，ST6GAL I添加了一种siAllyl转移酶，长期以来一直与结肠癌的进展/转移有关。我们的工作表明，ST6GAL I以及相应的整联蛋白α2-6溶解度在具有致癌性RA的肿瘤细胞系以及人类结肠肿瘤中上调。体外研究进一步表明，整联蛋白溶解在结肠肿瘤细胞的粘附，迁移和侵入性上具有明显的作用。为了更好地了解溶解度对整联蛋白结构/功能的贡献，以及整联蛋白溶解在肿瘤细胞转移中的潜在作用，我们提出了以下目的：特定目标1：位点特异性糖基化对整联蛋白构象和功能的影响。作为此目标的一部分，我们将表征整联蛋白的构象和功能，这些整合素的构素和功能使每个n-糖基化位点都烧蚀了。特定目标2：整联蛋白溶解对乳糖素3调节的细胞行为的影响。我们将研究整联蛋白溶解在调节GAL -3诱导的细胞反应中的作用，包括粘附，迁移，侵袭和凋亡。特定目标3：通过RAS定向差裂苷的调节转移相关细胞行为。这些研究旨在确定整联蛋白溶解是否在介导行为（如锚固无依赖性生长和侵袭等行为）中是RAS的下游效应子。特定目标4：整联蛋白溶解在促进裸鼠肿瘤生长和/或转移中的作用。我们将监测具有整合蛋白溶解水平的细胞的肿瘤发生和转移。