MDM2 regulates XIAP gene expression in cancer treatment

MDM2 在癌症治疗中调节 XIAP 基因表达

• 批准号: 7372276
• 负责人: MUXIANG ZHOU
• 金额: $ 25.67万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7372276
• 关键词: Address; Advanced Malignant Neoplasm; Apoptosis; Apoptotic; BIRC4 gene; Binding; Binding Sites; Cancer Patient; Cell Nucleus; Cell Survival; Cellular Stress; Complementary RNA; Cytoplasm; Data; Development; Dissociation; Drug resistance; Failure; Gene Expression; Goals; Internal Ribosome Entry Site; Knowledge; Lead; Link; Localized; MDM2 gene; MDM2 gene; Malignant Neoplasms; Maps; Mediating; Messenger RNA; Molecular; New Agents; Oncogene Deregulation; Oncogenes; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Protein Dephosphorylation; Protein Overexpression; Proteins; RNA; Radiation; Radiation therapy; Refractory; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Stress; TP53 gene; Testing; Therapeutic Agents; Trans-Activators; Translations; Up-Regulation; X-linked IAP; anticancer treatment; aptamer; base; cancer cell; cancer therapy; chemotherapy; design; inhibitor-of-apoptosis protein; inhibitor/antagonist; innovation; knowledge base; neoplastic cell; novel; novel strategies; novel therapeutics; response; tumorigenesis

DESCRIPTION (provided by applicant): A major cause for the failure of cancer treatment is the resistance of cancer cells to radiotherapy and chemotherapy, which is believed to be due to abnormal expression and deregulation of oncogenes or anti-apoptotic factors, or most likely a combination of these. We have found that the inhibitor-of-apoptosis protein XIAP is upregulated by the overexpression of the MDM2 oncogene during cancer treatment, and it has been linked to cancer cell survival and resistance to apoptosis following radiation and chemotherapy. It is also already known that MDM2 in the nucleus and its phosphorylated form, which is regulated by PI3K/Akt survival signaling, can bind to and inhibit p53 activity. In addition, MDM2 exerts a p53-independent role in oncogenesis by mechanisms that are not completely understood. The goals of this project are to determine the p53- independent role of MDM2 in regulating XIAP translation in the development of drug resistance during cancer therapy and to evaluate the potential for targeting the MDM2-XIAP signaling pathway for use in the treatment of drug-resistant cancer patients. Preliminary studies have demonstrated that, in response to radiation, MDM2 is dephosphorylated and localized in the cytoplasm, where it can directly elevate XIAP protein levels. The proposed study seeks to further clarify the molecular mechanisms by which stress stimulation, including radiation and chemotherapy, modulates MDM2 and subsequently induces XIAP translation as well as to establish the linkage between MDM2's regulation of XIAP translation at the cellular level and the patient population's response to anticancer treatment. The specific aims of this project are: 1) To investigate the p53-independent role of MDM2 in regulating XIAP translation through an internal ribosome entry site (IRES)-dependent pathway and to characterize the interaction between the MDM2 protein and XIAP IRES; 2) To determine the link between MDM2-mediated XIAP translation and the response to cellular stress signaling triggered by anticancer treatment; 3) To target the MDM2 protein/XIAP mRNA interaction in order to inhibit XIAP translation, towards developing a novel approach to cancer treatment. Because the survival of various types of cancer patients whose neoplastic cells overexpress MDM2 remains very poor, our studies may help generate knowledge that can extend our current understanding of resistance to radiotherapy and chemotherapy and provide the basic framework for the rational design of new agents that can be used to treat these refractory cancer patients. More knowledge-based ways to treat patients with resistant and advancing cancers are greatly needed in the anticancer therapy arsenal. Our research should help pave a new path towards some of these much needed treatments for patients with refractory cancers.

描述（申请人提供）：癌症治疗失败的一个主要原因是癌细胞对放疗和化疗的抵抗，这被认为是由于癌基因或抗凋亡因子的异常表达和失调，或者很可能是由于这些的组合。我们发现，在癌症治疗过程中，细胞凋亡抑制剂蛋白 XIAP 会因 MDM2 癌基因的过度表达而上调，并且它与放疗和化疗后癌细胞的存活和细胞凋亡抵抗力有关。众所周知，细胞核中的 MDM2 及其磷酸化形式受 PI3K/Akt 存活信号传导调节，可以结合并抑制 p53 活性。此外，MDM2 在肿瘤发生中发挥独立于 p53 的作用，其机制尚不完全清楚。该项目的目标是确定 MDM2 在癌症治疗期间耐药性发展中调节 XIAP 翻译的独立于 p53 的作用，并评估靶向 MDM2-XIAP 信号通路用于治疗耐药性的潜力癌症患者。初步研究表明，在辐射反应中，MDM2 去磷酸化并定位于细胞质中，可直接升高 XIAP 蛋白水平。拟议的研究旨在进一步阐明应激刺激（包括放疗和化疗）调节 MDM2 并随后诱导 XIAP 翻译的分子机制，并建立 MDM2 在细胞水平上对 XIAP 翻译的调节与患者群体对 XIAP 翻译的反应之间的联系。抗癌治疗。该项目的具体目标是： 1) 研究 MDM2 在通过内部核糖体进入位点 (IRES) 依赖性途径调节 XIAP 翻译中的独立于 p53 的作用，并表征 MDM2 蛋白和 XIAP IRES 之间的相互作用； 2) 确定MDM2介导的XIAP翻译与抗癌治疗触发的细胞应激信号反应之间的联系； 3) 靶向MDM2蛋白/XIAP mRNA相互作用以抑制XIAP翻译，开发一种新的癌症治疗方法。由于肿瘤细胞过度表达 MDM2 的各类癌症患者的生存率仍然很低，因此我们的研究可能有助于产生知识，从而扩展我们目前对放疗和化疗耐药性的理解，并为合理设计新药物提供基本框架。用于治疗这些难治性癌症患者。抗癌治疗库中非常需要更多基于知识的方法来治疗耐药性和进展性癌症患者。我们的研究应该有助于为难治性癌症患者提供一些急需的治疗方法铺平新的道路。