Role of HOS in cell transformation and apoptosis

HOS在细胞转化和凋亡中的作用

• 批准号: 6710682
• 负责人: Serge Y Fuchs
• 金额: $ 27.34万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2005-07-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6710682
• 关键词: I kappa B beta; apoptosis; breast neoplasms; camptothecin; cell adhesion; cell transformation; cisplatin; enzyme activity; ligase; neoplasm /cancer pharmacology; nuclear factor kappa beta; phosphoproteins; radiation sensitivity; tissue /cell culture; ubiquitin

In studying the mechanisms of targeting proteins for ubiquitination, Dr. Fuks identified HOS, a human homologue of Drosophila Slimb protein, as a key factor in recruitment of SCF E3 ubiquitin ligase to phosphorylated substrates including I-kappa-B and beta-catenin. They have demonstrated that alteration of HOS function affects stability of these proteins and NF-kappa-B- and Tcf-dependent transcriptional output. Their preliminary data also show that HOS is overexpressed in human tumor cell lines and primary human and mouse tumors as well as in normal cells in response to mitogens and oncogenic Ras. It is their working hypothesis that HOS, through its ability to recognize phosphorylated substrates and target them for SCF-Roc1-dependent ubiquitination, is an important regulator of cell proliferation, malignant transformation and programmed cell death. They propose to delineate the mechanisms and requirements for substrate recognition and SCF recruitment by HOS. Their second goal is to find out how HOS is regulated in human cells. They will analyze how HOS is regulated via its expression, stability and tyrosine phosphorylation. Finally, they will explore the role of HOS in modulation of the cellular functions of HOS substrates (I?B and beta-catenin) as per the changes in cell growth and transformation, and the programmed cell death. In all, the proposed studies will provide new understanding of HOS function, its role in human tumorigenesis and characterize HOS as a putative therapeutic target.

研究靶向蛋白质的机制 泛素化，福克斯博士确定了果蝇的人类同源物Hos 蛋白质，是募集SCF E3泛素连接酶的关键因素 磷酸化的底物在内，包括I-kappa-b和β-catenin。他们有 证明HOS功能的改变会影响这些的稳定性 蛋白质和NF-KAPPA-B-和TCF依赖性转录输出。他们的 初步数据还表明，HOS在人类肿瘤细胞系中过表达 以及原发性人和小鼠肿瘤以及正常细胞中的响应 有丝分裂剂和致癌性RA。 HOS是他们的工作假设 它具有识别磷酸化底物并将其靶向的能力 SCF-ROC1依赖性泛素化是细胞的重要调节剂 增殖，恶性转化和程序性细胞死亡。他们建议 描述底物识别和SCF的机制和要求 Hos招募。他们的第二个目标是找出如何调节HOS 人类细胞。他们将通过其表达来分析HOS如何调节 稳定性和酪氨酸磷酸化。最后，他们将探索 HOS调制了HOS底物的细胞函数（I？b和 β-catenin）根据细胞生长和转化的变化，以及 程序性细胞死亡。总的来说，拟议的研究将提供新的 了解HOS功能，其在人类肿瘤发生中的作用并表征 HOS作为推定的治疗靶标。