Regulation of Cell Function by Matricellular Hevin

基质细胞 Hevin 对细胞功能的调节

• 批准号: 7407527
• 负责人: Thomas N Wight
• 金额: $ 34.48万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-29 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407527
• 关键词: Accounting; Address; Adhesions; Adult; Amino Acids; Animals; Apoptosis; Architecture; Binding; Blood Vessels; Bos taurus; Carbohydrates; Cattle; Cell Adhesion; Cell Communication; Cell Cycle; Cell Cycle Inhibition; Cell Cycle Progression; Cell Proliferation; Cell physiology; Cell surface; Cells; Characteristics; Class; Closure; Collagen; Complex; Connective Tissue; Correlative Study; Coupled; Cysteine; Data; Dermal; Destinations; Development; Disease; Down-Regulation; Drosophila chb protein; Employee Strikes; Endothelial Cells; Endothelium; Exhibits; Extracellular Matrix; Face; Family; Fatty acid glycerol esters; Fibroblasts; Fibronectins; Financial compensation; Focal Adhesions; Follistatin; Gene Targeting; Genes; Genetic; Glycoproteins; Growth; Homologous Gene; Human; In Vitro; Inflammatory; Invasive; Knockout Mice; Knowledge; Label; Malignant Neoplasms; Measures; Mediating; Metabolic; Modeling; Molecular; Molecular Target; Molecular Weight; Morphogenesis; Mus; N-terminal; Neoplasm Metastasis; Nuclear; Null Lymphocytes; Oncogenic; Papilloma; Peptides; Permeability; Phage Display; Phenotype; Phosphorylation; Physiologic pulse; Post-Translational Protein Processing; Production; Protein Inhibition; Proteins; Pulse taking; Rate; Regulation; Relative (related person); Research Personnel; Retroviral Vector; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Running; S-Phase Fraction; Seminal; Stromal Cells; Structure; Surface Plasmon Resonance; Telomerase; Tenascin; Tertiary Protein Structure; Testing; Thrombospondin 1; Tissues; Transcript; Tumor Cell Line; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Tissue; Wild Type Mouse; Wound Healing; adhesion receptor; angiogenesis; base; cell growth; extracellular; fetal; genetic element; hevin; in vivo; injury and repair; insight; macrophage; member; monolayer; mutant; neoplastic cell; osteopontin; programs; receptor binding; relating to nervous system; research study; secretion process; tumor; tumor growth; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): This application addresses the structure, regulation, and function of the matricellular protein hevin, a relatively understudied member of the SPARC (secreted protein acidic and rich in cysteine) family of secreted glycoproteins. Also known as SC-1, MAST 9, SPARC-like 1, and ECM2, hevin has been described as a tumor-suppressor gene that also features prominently in the development and morphogenesis of certain tissues. In vitro, hevin has demonstrated deadhesive activity and enhancement of endothelial monolayer permeability, effects mediated in part by its diminishment of focal adhesion complexes in these cells. Despite recent provocative data regarding the association of hevin with tumor cell proliferation and/or metastasis, mechanisms accounting for these activities have remained elusive. We propose that hevin acts as a deadhesive, anti-proliferative matricellular protein that suppresses the growth of certain tumors via its modulation of tumor-stromal cell interactions. Accordingly, experiments described in this proposal test 3 hypotheses, based on our current understanding of hevin structure and function: 1) Selective deadhesion, cell-cycle inhibition, and regulation of extracellular matrix (ECM) production control specific aspects of tissue repair/angiogenesis and tumor progression. In Aim 1, we examine mechanisms governing these activities, as well as a cell-surface receptor/binding partner for hevin. 2) Regulation of the hevin gene and its posttranslational modifications are critical to our understanding of how hevin might act as a tumor suppressor. Aim 2 addresses these parameters in the context of tumor cell growth and angiogenesis in vitro. 3) There is both tissue tumor-specific and protein domain-specific compensation between hevin and its homolog SPARC, but hevin also has unique functions. Aim 3 features mice with targeted deletions of SPARC, hevin, and SPARC plus hevin, coupled with domain swaps between the two proteins, to evaluate the effect of hevin on tumor growth and metastasis in vivo. From an elucidation of molecular mechanisms by which hevin exerts its various regulatory activities on normal and tumor cells in vitro, we predict a better understanding of tumor-host stromal cell interactions in vivo, and the role of the matricellular protein hevin therein.

描述（由申请人提供）：此申请介绍了矩阵蛋白Hevin的结构，调节和功能，该蛋白质hevin是SPARC（分泌的蛋白质酸性和富含半胱氨酸）家族的分泌糖蛋白的相对研究的成员。 Hevin也称为SC-1，桅杆9，SPARC样1和ECM2，被描述为一种肿瘤抑制基因，在某些组织的发育和形态发生中也具有显着特征。 在体外，赫文表现出了死笼活性和内皮单层渗透性的增强，部分原因是由于其在这些细胞中局灶性粘附复合物的减少而介导的。 尽管最近关于Hevin与肿瘤细胞增殖和/或转移的相关性的挑衅性数据，但考虑到这些活动的机制仍然难以捉摸。 我们认为Hevin充当了一种死相关的抗增殖性母细胞蛋白，可通过调节某些肿瘤的肿瘤 - 块状细胞相互作用来抑制某些肿瘤的生长。 因此，基于我们当前对HEVIN结构和功能的理解，在本提案测试中描述的3个假设中描述的实验：1）选择性致命，细胞周期抑制以及细胞外基质（ECM）生产控制组织修复/血管生成和肿瘤进展的特定方面的调节。 在AIM 1中，我们检查了控制这些活动的机制，以及Hevin的细胞表面受体/结合伴侣。 2）调节Hevin基因及其翻译后修饰对于我们对Hevin如何充当肿瘤抑制剂的理解至关重要。 AIM 2在体外肿瘤细胞生长和血管生成的背景下解决了这些参数。 3）在Hevin及其同源性SPARC之间既有组织肿瘤特异性和蛋白质结构域特异性补偿，但Hevin也具有独特的功能。 AIM 3具有靶向缺失的小鼠SPARC，HEVIN和SPARC PLUS HEVIN，以及两种蛋白质之间的域交换，以评估Hevin对体内肿瘤生长和转移的影响。 从阐明赫文在体外对正常和肿瘤细胞上发挥其各种调节活性的分子机制，我们可以更好地理解体内肿瘤宿主霍斯特基质细胞相互作用，以及其中的母细胞蛋白hevin的作用。