p53, possibly the single most important human tumor suppressor, has been found to be mutated in over half of all cancers. This study investigates the role insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) plays in mediating p53-induced apoptosis and cell cycle arrest. p53 has been shown to activate IGFBP-3 expression and apoptosis, and the p53-induced apoptosis can be reversed by treatment with IGF-1 and by IGFBP-3 blockade. IGFBP-3 is integrally involved in apoptosis as well as in growth inhibition, acting in both IGF-dependent and independent manners. The central hypothesis, that p53-induced apoptosis is mediated in part by the actions of IGFBP-3, underscores the experimental goals: to evaluate the physiologic significance of the p53/IGFBP-3 interaction and to elucidate its mechanisms of action. The mechanisms investigated will include the promoter sequences necessary for IGFBP-3 induction by genotoxic stress and hypoxia, the downstream effectors of IGFBP-3-mediated apoptosis and the IGFBP-3 domains required for inducing apoptosis. The possibility that IGFBP-3 is not the only IGFBP regulated by p53 will be explored. If successful, these studies may provide further understanding of the molecular events leading to apoptosis and delineate new means of cross-talk between the p53 and IGF axes. This is particularly important for diseases of dysregulated cell growth, given the recent findings of an association between elevated serum IGF-1 levels and increased risk of prostate, colorectal and lung cancer. Clarifying the role of IGFBP-3 mediated apoptosis as a protective factor may not only help to understand the significance of the IGF-1 association, but may also suggest novel approaches to the treatment and clinical management of cancer and other diseases involving dysregulated cell growth. These studies also reflect Dr. Grimberg?s long-term career goals of exploring the interrelatedness of endocrine and oncologic molecular biology principles and applying them to clinical problems of dysregulated growth.
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