BAG3 AS A REGULATOR OF CELL MOTILITY

BAG3 作为细胞运动的调节剂

• 批准号: 6783741
• 负责人: SHINICHI TAKAYAMA
• 金额: $ 5.54万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2004-06-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6783741
• 关键词: 3T3 cells; SCID mouse; actins; apoptosis; athymic mouse; autoradiography; biological signal transduction; biomarker; cell motility; cell proliferation; cytoskeleton; gene expression; heat shock proteins; immunofluorescence technique; immunoprecipitation; mass spectrometry; metastasis; molecular chaperones; neoplasm /cancer invasiveness; neoplastic transformation; protein protein interaction; protooncogene; tissue /cell culture; transport proteins; western blottings

DESCRIPTION (provided by applicant): BAG3 binds to and regulates Hsp70 function (Takayama, et al. J Biol Chem 274: 781, 1999). The BAG3 protein contains a WW domain and a proline-rich region with SH3-binding motifs, suggesting that it may interact with proteins relevant to submembranous signal transduction, recruiting Hsp70 to signaling complexes and altering cell responses. BAG3 binds to several cellular proteins including a GDP Exchange Factor (GEF) and SH3-containing signal transducing proteins, in addition to 70-kDa heat shock proteins. BAG3 over-expression in Balb/c 3T3 fibroblasts induces transformation and BAG3 over-expression has been observed in human cancers, especially pancreatic cancer. We speculate therefore that BAG3 represents a novel proto-oncogene that may affect cell transformation, anchorage-independent growth, or other processes relevant to the malignant phenotype. Also we have found that BAG3 over-expression increases motility of Cos7 cell. Moreover, homozygous bag3 deficient mouse embryonic fibroblasts exhibit dysregulation of actin cytoskeleton and abnormal motility. Experiments are proposed to explore the molecular mechanism of the BAG3 protein. (1) Investigating how BAG3 controls cytoskeleton and determining what domains of BAG3 are required including; (2) Exploring the functional significance of interactions of BAG3 with GEF, SH3 proteins and Hsp70 proteins; and (3) Exploring BAG3 expression in cancer and its role in malignant transformation. These studies will provide insights into the oncogenic properties of BAG3 and may assist in finding new targets for cancer therapy.

描述（由申请人提供）： BAG3与Hsp70结合并调节其功能（Takayama等，J Biol Chem 274：781，1999）。BAG3蛋白含有WW结构域和富含脯氨酸的区域，该区域具有SH3结合基序，这表明它可能与膜下信号转导相关的蛋白质相互作用，将Hsp70募集到信号复合物中并改变细胞反应。BAG3结合几种细胞蛋白，包括GDP交换因子（GEF）和含SH3的信号转导蛋白，以及70-kDa热休克蛋白。BAG3在Balb/c 3T3成纤维细胞中的过表达诱导转化，并且已经在人类癌症，特别是胰腺癌中观察到BAG3过表达。因此，我们推测BAG 3代表一种新型原癌基因，可能影响细胞转化、非贴壁依赖性生长或其他与恶性表型相关的过程。我们还发现BAG3过表达增加了Cos7细胞的运动性。此外，纯合子bag3缺陷小鼠胚胎成纤维细胞表现出肌动蛋白细胞骨架和异常运动失调。实验拟探讨BAG3蛋白的分子机制。(1)研究BAG3如何控制细胞骨架并确定需要BAG3的哪些结构域，包括：（2）探索BAG3与GEF，SH3蛋白和Hsp70蛋白相互作用的功能意义;（3）探索BAG3在癌症中的表达及其在恶性转化中的作用。这些研究将提供对BAG 3致癌特性的深入了解，并可能有助于寻找癌症治疗的新靶点。