Role of IGFBP -3 in mediating p53-induced apoptosis

描述(申请人提供)：P53，可能是最重要的一个 人类肿瘤抑制基因，已被发现在超过一半的所有肿瘤中发生突变 癌症。本研究探讨胰岛素样生长因子(IGF)的作用。 结合蛋白-3(IGFBP-3)在介导P53诱导的细胞凋亡和细胞凋亡中的作用 周期拘禁。已有研究表明，p53可以激活IGFBP-3的表达，并 细胞凋亡，P53诱导的细胞凋亡可被逆转 IGF-1和IGFBP-3阻断。IGFBP-3与细胞凋亡密切相关 以及生长抑制，既作用于IGF依赖的，也作用于IGF独立的 礼貌。核心假设是，P53诱导的细胞凋亡是通过 通过IGFBP-3的行动，强调了实验目标： 评价P53/IGFBP-3相互作用的生理学意义 阐明其作用机制。被调查的机制将包括 基因毒性应激诱导IGFBP-3所需的启动子序列 低氧、IGFBP-3介导的细胞凋亡下游效应因子及IGFBP-3 诱导细胞凋亡所需的结构域。IGFBP-3可能是 不是唯一受P53调控的IGFBP将被探索。如果成功，这些 研究可能会提供对导致 并勾勒出P53和IGF轴之间相互作用的新途径。 这对于细胞生长失调的疾病尤其重要，因为 血清IGF-1水平升高与胰岛素样生长因子相关的最新发现 前列腺癌、结直肠癌和肺癌的风险增加。澄清角色 IGFBP-3介导的细胞凋亡作为保护因素不仅有助于 理解IGF-1关联的意义，但也可能建议 癌症和其他疾病的治疗和临床管理的新方法 涉及细胞生长失调的疾病。这些研究也反映了Dr。 格林伯格？S的长期职业生涯目标是探索 内分泌和肿瘤学分子生物学原理及其在临床中的应用 生长失调的临床问题。

DESCRIPTION (provided by applicant): 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.