Regulation of Cell Function by Matricellular Hevin

基质细胞 Hevin 对细胞功能的调节

• 批准号: 7228904
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228904
• 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）：本申请涉及基质细胞蛋白hevin的结构、调节和功能，hevin是分泌糖蛋白的分泌蛋白（分泌蛋白，酸性且富含半胱氨酸）家族中研究相对不足的成员。 hevin也被称为SC-1、MAST 9、SPARC样1和ECM 2，已被描述为肿瘤抑制基因，其在某些组织的发育和形态发生中也具有显著特征。 在体外，hevin已被证明具有去粘附活性和增强内皮单层通透性，其作用部分通过减少这些细胞中的粘着斑复合物来介导。 尽管最近的挑衅性的数据与肿瘤细胞增殖和/或转移的关联hevin，占这些活动的机制仍然难以捉摸。 我们认为，hevin作为一种脱粘，抗增殖的基质细胞蛋白，通过调节肿瘤基质细胞的相互作用抑制某些肿瘤的生长。 因此，基于我们目前对hevin结构和功能的理解，本提案中描述的实验测试了3种假设：1）选择性去粘附，细胞周期抑制和细胞外基质（ECM）产生的调节控制组织修复/血管生成和肿瘤进展的特定方面。 在目标1中，我们研究了这些活动的机制，以及hevin的细胞表面受体/结合伴侣。 2)hevin基因的调控及其翻译后修饰对于我们理解hevin如何作为肿瘤抑制因子至关重要。 目的2在体外肿瘤细胞生长和血管生成的背景下解决这些参数。 3)hevin与其同源物hevin之间既有组织肿瘤特异性补偿，也有蛋白质结构域特异性补偿，但hevin也有其独特的功能。 目的3：研究hevin、hevin和hevin + hevin靶向缺失的小鼠，结合两种蛋白质之间的结构域交换，以评估hevin对体内肿瘤生长和转移的影响。 从阐明hevin发挥其在体外正常细胞和肿瘤细胞的各种调节活动的分子机制，我们预测更好地了解肿瘤宿主基质细胞在体内的相互作用，以及基质细胞蛋白hevin在其中的作用。