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: 8629704
• 负责人: MUXIANG ZHOU
• 金额: $ 24.37万
• 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/8629704
• 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）：MDM 2是一种重要的癌症相关蛋白，其通过p53依赖性和非依赖性信号通路诱导癌细胞存活和进展。在先前的研究中，我们发现MDM 2的p53非依赖性作用，癌蛋白MDM 2可以增加抗凋亡因子XIAP的表达，通过MDM 2的RING结构域结合XIAP IRES mRNA，诱导其翻译活性。我们对该更新申请的初步研究表明，当XIAP IRES结合MDM 2 RING结构域蛋白时，MDM 2蛋白稳定性增加。基于这些发现，我们认为XIAP IRES和MDM 2的RING结构域之间的结合作用可以同时增加XIAP和MDM 2的表达，分别通过激活IRES依赖性翻译和抑制蛋白质降解。在癌细胞中，MDM 2和XIAP的表达增加可能有助于癌症进展或对抗癌治疗的抗性。因此，我们假设这种分子相互作用的抑制将导致MDM 2和XIAP表达的同时降低，从而不仅抑制癌症，而且逆转治疗期间的耐药性。该项目的目标是：鉴定可以破坏MDM 2蛋白/XIAP IRES相互作用的小分子抑制剂，表征鉴定的MDM 2/XIAP抑制剂是否能够诱导MDM 2自身泛素化和降解以及抑制XIAP翻译，并确定鉴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。具体而言，目标1是进行HTS以选择阻断或破坏XIAP IRES mRNA与MDM 2的RING结构域蛋白之间相互作用的小分子化合物;目标2将研究所选MDM 2/XIAP抑制剂如何在分子水平上破坏这种相互作用，并找到抑制剂靶向MDM 2降解的作用机制。对于目标3，我们将检查MDM 2降解和XIAP翻译的抑制通过选定的化合物对体外癌细胞生长和凋亡的影响，加上在动物模型中进行翻译研究，以确定这些鉴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MDM 2和XIAP，并且他们的生存率仍然很低，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。