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功能结合并调节（Takayama等人，J Biol Chem 274：781，1999）。 BAG3蛋白包含一个具有SH3结合基序的WW结构域和富含脯氨酸的区域，这表明它可能与与肿瘤信号转导相关的蛋白质相互作用，将HSP70募集到信号传导复合物和改变细胞反应。 BAG3与几种细胞蛋白结合，包括GDP交换因子（GEF）和含SH3的信号转导蛋白，此外还具有70 kDA热激蛋白。 BALB/C 3T3成纤维细胞中的BAG3过表达可引起转化，并且在人类癌症（尤其是胰腺癌）中观察到了BAG3过表达。因此，我们推测BAG3代表了一种新型的原始癌基因，可能会影响细胞转化，独立的生长或与恶性表型相关的其他过程。我们还发现，BAG3的过表达增加了COS7细胞的运动性。此外，纯合子BAG3缺乏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的失调。提出了实验来探索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哪些BAG3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）探索癌症中的BAG3表达及其在恶性转化中的作用。这些研究将为BAG3的致癌特性提供见解，并可能有助于寻找癌症治疗的新靶标。