Altered Proteoglycan Gene Expression and Cancer

蛋白多糖基因表达改变与癌症

基本信息

批准号：
7909761
负责人：
RENATO V. IOZZO
金额：
$ 14.51万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7909761
关键词：
Address Affect Animal Model Animals Attenuated Basic Cancer Research Binding Biological Biology Breast Carcinoma Carcinoma Cell Proliferation Cells Chimera organism Complement Core Protein Cytostatics Development Dimerization Docking EGF gene ERBB2 gene Ectopic Expression Engineering Epidermal Growth Factor Receptor Event Family Five-Year Plans Future Generations Goals Green Fluorescent Proteins Growth Growth Factor Invaded Knowledge Lead Learning Ligand Binding Ligands Light Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Metastatic Neoplasm to the Lung Molecular Molecular Conformation Neoplasm Metastasis Oncogenic Pathway interactions Protein Tyrosine Kinase Proteins Proteoglycan Receptor Activation Recombinant Proteins Research Role Series Signal Transduction Site-Directed Mutagenesis TP53 gene Testing Thymic Lymphoma Time Tumorigenicity Work adeno-associated viral vector attenuation base cancer gene expression cancer prevention cell growth cell transformation cellular engineering crosslink decorin design in vivo inhibitor/antagonist interdisciplinary approach loss of function member mimetics mutant neoplastic cell novel prevent receptor receptor function response theories tumor tumor growth tumor progression tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to elucidate the mechanism of action of decorin in controlling cell proliferation. The central hypothesis is that decorin is a natural antagonist of cancer growth, a working theory based on several key observations: [a] Decorin levels are suppressed in most transformed cells, but markedly increased in quiescent cells. [b] Animals harboring a targeted disruption of decorin and p53 genes die rapidly of thymic lymphomas, indicating that lack of decorin is permissive for tumorigenesis. [c] Ectopic expression of decorin induces profound cytostatic effects in a wide variety of transformed cells. [d] Decorin interacts with the epidermal growth factor receptor (EGFR) and causes a profound attenuation of its tyrosine kinase activity, thereby leading to growth inhibition. Over the next five years we plan to continue the studies on the biology of mammalian decorin and decode the molecular mechanisms through which decorin exerts its cytostatic functions. Specifically, we plan to: (1) Decipher the mechanism of action of decorin in suppressing EGFR activity. (2) Determine the precise structural requirements for decorin/EGFR interaction, and (3) Investigate the in vivo function of decorin as an anti-oncogenic factor. These concerted research lines should firmly establish the functional roles of decorin in tumorigenicity and shed light on its mechanism of action. The discovery that decorin is a novel biological ligand for the EGFR and that this interaction leads to an overt attenuation of the EGFR kinase and signaling provides the first demonstration of a secreted proteoglycan interacting with this important signal transducing pathway. The expected results could open novel perspectives for basic cancer research, and could lead to future approaches of cancer prevention and treatment directed at boosting the expression of this proteoglycan, thereby increasing a natural inhibitor of tumor cell growth.

描述（由申请人提供）：该提案的长期目标是阐明Decorin在控制细胞增殖中的作用机理。中心假设是Decorin是癌症生长的天然拮抗剂，这是基于几个关键观察的工作理论：[A]在大多数转化的细胞中抑制了Decorin水平，但在静态细胞中显着增加。 [b]具有靶向破坏装饰蛋白和p53基因的动物迅速死于胸腺淋巴瘤，表明缺乏dorigonin是允许肿瘤发生的。 [C] Decorin的异位表达在多种转化的细胞中诱导了深刻的细胞抑制作用。 [d] Decorin与表皮生长因子受体（EGFR）相互作用，并引起其酪氨酸激酶活性的严重衰减，从而导致生长抑制作用。在接下来的五年中，我们计划继续对哺乳动物装饰的生物学进行研究，并解码DecorIn发挥其细胞抑制功能的分子机制。具体而言，我们计划：（1）破译Decorin在抑制EGFR活动中的作用机理。（2）确定Decorin/eGFR相互作用的精确结构要求，（3）研究Decorin作为抗结构因子的体内功能。这些协同的研究线应牢固确定dorighin在肿瘤性中的功能作用，并阐明其作用机理。 Decorin是EGFR的一种新型生物配体的发现，并且这种相互作用导致EGFR激酶和信号传导的明显衰减提供了与这一重要信号转导途径相互作用的第一次证明。预期的结果可能会为基本癌症研究开辟新的观点，并可能导致预防癌症预防和致力于增强该蛋白聚糖表达的治疗方法，从而增加自然的肿瘤细胞生长抑制剂。