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Nuclear Insulin-Like Growth Factor Binding Protein-3 Induces Apoptosis and Is Targeted to Ubiquitin/Proteasome–Dependent Proteolysis

¹ Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck, Austria; ² Tumorvirology Laboratory, Tyrolean Cancer Research Institute; and ³ Institute of Pathology, Medical University of Innsbruck, Austria; ⁴ Division of Molecular and Cell Biology, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck, Austria; and ⁵ Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales, Australia

Requests for reprints: Werner Zwerschke, Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research, Rennweg 10, 6020 Innsbruck, Austria. Phone: 43-512-5839-1932; Fax: 43-512-583-9198; E-mail: werner.zwerschke{at}oeaw.ac.at.

Insulin-like growth factor binding protein-3 (IGFBP-3), the product of a tumor suppressor target gene, can modulate cell proliferation and apoptosis by IGF-I-dependent and IGF-I-independent mechanisms. IGFBP-3 controls the bioavailability of IGFs in the extracellular environment and is known to be subject to degradation by various extracellular proteases. Although nuclear localization and functions of IGFBP-3 have been described in the past, we show as the novel features of this study that the abundance of nuclear IGFBP-3 is directly regulated by ubiquitin/proteasome–dependent proteolysis. We show that IGFBP-3 degradation depends on an active ubiquitin-E1 ligase, specific 26S proteasome inhibitors can efficiently stabilize nuclear IGFBP-3, and the metabolic half-life of nuclear IGFBP-3 is strongly reduced relative to cytoplasmic IGFBP-3. Nuclear IGFBP-3 is highly polyubiquitinated at multiple lysine residues in its conserved COOH-terminal domain and stabilized through mutation of two COOH-terminal lysine residues. Moreover, we show that IGFBP-3, if ectopically expressed in the nucleus, can induce apoptotic cell death. These results suggest that ubiquitin/proteasome–mediated proteolysis of IGFBP-3 may contribute to down-regulation of apoptosis. (Cancer Res 2006; 66(6): 3024-33)

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