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（由申请人提供）：癌症治疗失败的主要原因是癌细胞对放疗和化学疗法的抗性，这被认为是由于异常表达和对癌基因或抗凋亡因素的失调，或者很可能是其中的组合。我们发现，在癌症治疗期间，MDM2癌基因的过表达抑制了凋亡蛋白XIAP，并且与放射和化学疗法后的癌细胞存活和对凋亡的抗性有关。还已经知道，核中的MDM2及其磷酸化形式受PI3K/AKT存活信号调节，可以与p53活性结合并抑制p53活性。此外，MDM2通过未完全理解的机制在肿瘤发生中扮演p53独立的作用。该项目的目标是确定MDM2在调节XIAP翻译中在癌症治疗过程中耐药性发展中的独立作用，并评估靶向MDM2-XIAP信号传导途径的潜力，用于治疗抗药性癌症患者。初步研究表明，针对辐射，MDM2被脱磷酸化并定位在细胞质中，可以直接升高XIAP蛋白水平。拟议的研究旨在进一步阐明分子机制，通过这些机制，包括放射线和化学疗法在内的应激刺激调节MDM2并随后诱导XIAP翻译，并建立MDM2调节XIAP在细胞水平上的XIAP翻译调节与患者人群对抗癌治疗的反应之间的联系。该项目的具体目的是：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p53独立的作用，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的反应之间的联系； 3）靶向MDM2蛋白/XIAP mRNA相互作用，以抑制XIAP翻译，以开发一种新型的癌症治疗方法。由于肿瘤细胞过表达MDM2的各种类型的癌症患者的存活仍然非常差，因此我们的研究可能有助于产生知识，以扩展我们对放射治疗和化学疗法的耐药性的最新理解，并为可用于治疗这些难治性癌症患者的新药物的合理设计提供了基本框架。在抗癌疗法中，需要更多基于知识的方法来治疗耐药性和进步癌症的患者。我们的研究应该有助于为难治性癌症患者的一些急需的治疗铺平道路。