Role of HOS in cell transformation and apoptosis

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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.