The type 1 insulin-like growth factor receptor (IGF-IR) has recently become one of the favorite targets of industry for its possible role in the growth of normal and abnormal cells. IGF-IR signaling also plays a significant role in longevity, from C. elegans to mammalians. The IGF axis controls, in a non-redundant way, about 50% of growth in animals and cells in culture, largely through the activation of its docking protein, the insulin receptor substrate-1 (IRS-1). Deletion of IRS-1 (or its homologues in Drosophila) results in animals or cells that are roughly 50% in size. We have recently found that IRS-1 translocates to the nuclei where it binds and activates UBF1 (Upstream Binding Factor 1), a protein that regulates RNA polymerase I activity, and therefore cell (and body) size. In this application, we propose to study: 1) the mechanism by which IRS-1 regulates the activity and/or the stability of UBF1;2) the mechanism(s) by which nuclear IRS-1 competes with other nucleolar proteins for the activation of the ribosomal DNA promoter;and 3) the physical and biological interactions of IRS-1 with the SV40 T antigen and selected RNA polymerase-2-directed promoters n the nuclei of cells, an interaction that may be critical for the transformation of cells. These studies have a direct impact on our basic knowledge of the biology of cancer and may throw light on mechanisms of aging.
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