Regulation of MDM2 auto-ubiquitination and molecular targeting

MDM2 自动泛素化和分子靶向的调控

基本信息

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
项目类别：
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

项目摘要

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，它通过p53依赖性和非依赖性信号传导途径诱导癌细胞存活和进展。在之前对MDM2独立于p53的作用的研究中，我们发现癌蛋白MDM2可以通过MDM2的RING结构域与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。我们针对这一更新应用的初步研究表明，当 XIAP IRES 与 MDM2 RING 结构域蛋白结合时，MDM2 蛋白的稳定性增强。基于这些发现，我们认为 XIAP IRES 和 MDM2 RING 结构域之间的结合作用可以分别通过激活 IRES 依赖性翻译和抑制蛋白质降解来同时增加 XIAP 和 MDM2 的表达。在癌细胞中，MDM2 和 XIAP 表达增加可能有助于癌症进展或对抗癌治疗产生耐药性。因此，我们假设抑制这种分子相互作用将导致 MDM2 和 XIAP 表达同时下降，不仅抑制癌症，而且逆转治疗期间的耐药性。该项目的目标是：鉴定能够破坏 MDM2 蛋白/XIAP IRES 相互作用的小分子抑制剂，表征所鉴定的 MDM2/XIAP 抑制剂是否能够诱导 MDM2 自身泛素化和降解以及抑制 XIAP 翻译，并确定已确定的抑制剂作为能够治疗难治性癌症患者的新药的潜在用途。具体来说，目标1是进行HTS来选择阻断或破坏XIAP IRES mRNA与MDM2的RING结构域蛋白之间相互作用的小分子化合物；目标 2 将研究选定的 MDM2/XIAP 抑制剂如何在分子水平上破坏这种相互作用，并找到抑制剂针对 MDM2 降解的作用机制。对于目标 3，我们将研究选定化合物对 MDM2 降解和 XIAP 翻译抑制的体外癌细胞生长和凋亡的影响，并在动物模型中进行转化研究，以确定这些已确定的化合物作为临床上可行的抗癌药物。由于大量癌症患者的恶性细胞过度表达 MDM2 和 XIAP，且其生存率仍然很低，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物来治疗这些难治性癌症患者。