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疗的抗性，据信这是由于癌基因或抗凋亡因子的异常表达和失调，或很可能是这些的组合。我们已经发现，凋亡通道蛋白XIAP在癌症治疗过程中通过MDM 2癌基因的过表达而上调，并且它与放疗和化疗后的癌细胞存活和对凋亡的抵抗有关。还已知细胞核中的MDM 2及其磷酸化形式（其由PI 3 K/Akt存活信号传导调节）可以结合并抑制p53活性。此外，MDM 2在肿瘤发生中通过尚未完全理解的机制发挥p53非依赖性作用。该项目的目标是确定MDM 2在调节XIAP翻译中的p53非依赖性作用，从而在癌症治疗期间产生耐药性，并评估靶向MDM 2-XIAP信号通路用于治疗耐药性癌症患者的潜力。初步研究表明，在对辐射的反应中，MDM 2被去磷酸化并定位于细胞质中，在那里它可以直接升高XIAP蛋白水平。拟议的研究旨在进一步阐明应激刺激（包括放射和化疗）调节MDM 2并随后诱导XIAP翻译的分子机制，以及建立MDM 2在细胞水平上调节XIAP翻译与患者群体对抗癌治疗的反应之间的联系。本项目的具体目的是：1）研究MDM 2通过内部核糖体进入位点（IRES）依赖性途径在调节XIAP翻译中的p53非依赖性作用，并表征MDM 2蛋白与XIAP IRES之间的相互作用; 2）确定MDM 2介导的XIAP翻译与抗癌治疗引发的细胞应激信号传导之间的联系; 3）靶向MDM 2蛋白/XIAP mRNA相互作用以抑制XIAP翻译，从而开发癌症治疗的新方法。由于肿瘤细胞过度表达MDM 2的各种类型的癌症患者的生存率仍然很低，我们的研究可能有助于产生知识，可以扩展我们目前对放疗和化疗耐药性的理解，并为合理设计可用于治疗这些难治性癌症患者的新药物提供基本框架。在抗癌疗法中，非常需要更多基于知识的方法来治疗具有耐药性和进展性癌症的患者。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新的道路。