Regulation of MDM2 auto-ubiquitination and molecular targeting

MDM2 自动泛素化和分子靶向的调控

• 批准号: 8503289
• 负责人: MUXIANG ZHOU
• 金额: $ 25.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503289
• 关键词: Address; Adverse effects; Animal Model; Antineoplastic Agents; Apoptosis; Apoptotic; Applications Grants; BIRC4 gene; Binding; Biological Assay; C-terminal; Cancer Cell Growth; Cancer Patient; Caspase; Cell Survival; Cells; Characteristics; Chemicals; Development; Drug resistance; Goals; In Vitro; Internal Ribosome Entry Site; Investigation; Knowledge; Lead; Libraries; MDM2 gene; Malignant Neoplasms; Mediating; Messenger RNA; Modification; Molecular; Molecular Mechanisms of Action; Molecular Target; Oncogene Proteins; Pharmaceutical Preparations; Play; Protein Degradation Inhibition; Protein p53; Proteins; RNA; Refractory; Regulation; Resistance; Resistance development; Role; SCID Mice; Signal Pathway; Structure-Activity Relationship; Tertiary Protein Structure; Testing; Therapeutic; Translations; Ubiquitination; Untranslated Regions; Up-Regulation; X-linked IAP; anticancer activity; anticancer treatment; base; cancer cell; cancer therapy; chemotherapy; cytotoxic; in vivo; inhibitor/antagonist; innovation; killings; mouse model; novel; overexpression; preclinical study; public health relevance; response; small molecule; translational approach; translational study; tumor progression

DESCRIPTION (provided by applicant): MDM2 is an important cancer-related protein that induces cancer cell survival and progression through both p53-dependent and -independent signaling pathways. In previous investigations of the p53-independent role of MDM2, we found that the oncoprotein MDM2 can increase the expression of the anti-apoptotic factor XIAP through binding of MDM2's RING domain to the XIAP IRES mRNA, inducing its translational activity. Our preliminary studies for this renewal application demonstrated that when XIAP IRES bound to the MDM2 RING domain protein, MDM2 protein stabilization increased. Based on these findings, we believe that the binding action between XIAP IRES and the RING domain of MDM2 can simultaneously increase expression of XIAP and MDM2, through activation of IRES-dependent translation and by inhibition of protein degradation, respectively. In cancer cells, increased expression of both MDM2 and XIAP may aid cancer progression or resistance to anticancer treatment. Accordingly, we hypothesized that inhibition of this molecular interaction would result in a simultaneous decrease in the expression of both MDM2 and XIAP, leading to not only suppression of the cancer, but a reversal of drug resistance during therapy. The goals of this project are: to identify small molecule inhibitors that can disrupt the MDM2 protein/XIAP IRES interaction, to characterize whether the identified MDM2/XIAP inhibitors are able to induce MDM2 self-ubiquitination and degradation as well as inhibition of XIAP translation, and to ascertain the potential use of the identified inhibitors as new drugs able to treat refractory cancer patients. Specifically, Aim 1 is to perform HTS to select small-molecule compounds that block or disrupt the interaction between XIAP IRES mRNA and the RING domain protein of MDM2; Aim 2 will investigate how selected MDM2/XIAP inhibitors disrupt that interaction at the molecular level and find the mechanism of action by which the inhibitor targets MDM2 degradation. For Aim 3, we will examine the effects of MDM2 degradation and inhibition of XIAP translation by selected compounds on cancer cell growth and apoptosis in vitro, plus perform translational studies in animal models to ascertain these identified compounds as clinically viable anticancer drugs. Because a significant number of cancer patients have malignant cells that are overexpressing MDM2 and XIAP and their survival remains poor, we hope our studies will lead directly to the discovery of several useful new drugs to treat these refractory cancer patients.

描述（由申请人提供）：MDM2是一种重要的癌症相关蛋白，可通过p53依赖性和非依赖性信号通路诱导癌细胞的存活和进展。在先前对MDM2 p53独立作用的研究中，我们发现癌蛋白MDM2可以通过MDM2环域与XIAP IRES mRNA的结合来增加抗凋亡因子XIAP的表达，从而诱导其翻译活性。我们针对此更新应用的初步研究表明，当Xiap Ires与MDM2环域蛋白结合时，MDM2蛋白稳定会增加。基于这些发现，我们认为XIAP IRES与MDM2的环域之间的结合作用可以通过激活IRES依赖性翻译和抑制蛋白质降解，同时增加XIAP和MDM2的表达。在癌细胞中，MDM2和XIAP的表达增加可能有助于癌症进展或抗抗癌治疗。因此，我们假设抑制这种分子相互作用将导致MDM2和XIAP的表达同时降低，这不仅导致抑制癌症，而且导致治疗过程中耐药性的逆转。该项目的目标是：确定可能破坏MDM2蛋白/XIAP IRES相互作用的小分子抑制剂，以表征已鉴定的MDM2/XIAP抑制剂是否能够诱导MDM2自我泛素化并降解并抑制XIAP转换的毒药，并抑制识别的药物的适应性。具体而言，AIM 1是执行HTS以选择阻断或破坏XIAP IRES mRNA与MDM2的环域蛋白之间相互作用的小分子化合物； AIM 2将研究选择的MDM2/XIAP抑制剂如何破坏分子水平的这种相互作用，并找到抑制剂靶向MDM2降解的作用机理。对于AIM 3，我们将研究MDM2降解和通过选定化合物在体外对癌细胞生长和凋亡抑制XIAP翻译的影响，并在动物模型中进行转化研究以确定这些鉴定出的化合物为临床可行的抗癌药物。由于大量癌症患者的恶性细胞过表达MDM2和XIAP且其存活率仍然很差，因此我们希望我们的研究将直接导致发现几种有用的新药来治疗这些难治性癌症患者。