Role of HOS in cell transformation and apoptosis

在研究靶向蛋白质的机制， Fuks博士通过泛素化，确定了HOS，一种果蝇Slimb的人类同源物 蛋白，作为SCF E3泛素连接酶募集的关键因素， 磷酸化底物，包括I-κ-B和β-连环蛋白。他们有 证明了HOS功能的改变会影响这些细胞的稳定性， 蛋白质和NF-κ-B-和Tcf依赖性转录输出。他们的 初步数据还显示，HOS在人类肿瘤细胞系中过表达 以及在正常细胞中， 有丝分裂原和致癌Ras。他们的工作假设是， 它能够识别磷酸化底物并将其靶向 SCF-Roc 1依赖的泛素化，是一种重要的细胞调节因子， 增殖、恶性转化和程序性细胞死亡。他们提出 描述底物识别和SCF的机制和要求 招聘HOS他们的第二个目的是了解如何监管居屋， 人体细胞他们将分析HOS如何通过其表达进行调节， 稳定性和酪氨酸磷酸化。最后，他们将探讨 HOS在调节HOS底物的细胞功能中的作用（I？B和 根据细胞生长和转化的变化， 程序性细胞死亡总之，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， HOS作为假定的治疗靶点。

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.