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

2006; American Association for Cancer Research; Volume: 66; Issue: 6 Linguagem: Inglês

10.1158/0008-5472.can-05-2013

1538-7445

Frédéric R. Santer, Nicole Bacher, Barbara Moser, Dieter Morandell, Sigrun Ressler, Sue M. Firth, Gilles A. Spoden, Consolato Sergi, Robert C. Baxter, Pidder Jansen‐Dürr, Werner Zwerschke,

Cancer, Hypoxia, and Metabolism

Abstract 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)