Altered Proteoglycan Gene Expression and Cancer

蛋白多糖基因表达改变与癌症

• 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
• 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

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）：本提案的长期目标是阐明核心蛋白聚糖在控制细胞增殖中的作用机制。核心假设是核心蛋白聚糖是癌症生长的天然拮抗剂，这是一个基于几个关键观察的工作理论：[a]核心蛋白聚糖水平在大多数转化细胞中受到抑制，但在静止细胞中显着增加。[b]具有核心蛋白聚糖和p53基因的靶向破坏的动物迅速死于胸腺淋巴瘤，表明缺乏核心蛋白聚糖是允许肿瘤发生的。[c]核心蛋白聚糖的异位表达在多种转化细胞中诱导显著的细胞生长抑制作用。[d]核心蛋白聚糖与表皮生长因子受体（EGFR）相互作用，导致其酪氨酸激酶活性显著减弱，从而导致生长抑制。 在接下来的五年里，我们计划继续对哺乳动物核心蛋白聚糖的生物学进行研究，并解码核心蛋白聚糖发挥其细胞抑制功能的分子机制。具体而言，我们计划：（1）解密核心蛋白聚糖抑制EGFR活性的作用机制。(2)确定核心蛋白聚糖/EGFR相互作用的精确结构要求，和（3）研究核心蛋白聚糖作为抗癌因子的体内功能。 这些协调一致的研究路线应该牢固地建立核心蛋白聚糖在致瘤性中的功能作用，并阐明其作用机制。核心蛋白聚糖是EGFR的一种新型生物配体，这种相互作用导致EGFR激酶和信号传导的明显减弱，这一发现首次证明了分泌的蛋白聚糖与这种重要的信号转导途径相互作用。预期的结果可能为基础癌症研究开辟新的前景，并可能导致未来的癌症预防和治疗方法，旨在促进这种蛋白聚糖的表达，从而增加肿瘤细胞生长的天然抑制剂。