Novel oncogenic functions of Mdm2 and Mdmx

Mdm2 和 Mdmx 的新致癌功能

基本信息

批准号：
9493436
负责人：
CHRISTINE M. EISCHEN
金额：
$ 32.37万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-18 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9493436
关键词：
Apoptosis Binding Biological Cell Culture Techniques Cell Cycle Cell Cycle Checkpoint Cell Nucleus Cell Survival Cells Chromatin Complex DNA DNA Damage DNA Repair Data Development Family member Genome Stability Genomic Instability Grant Heterodimerization Human Intervention Investigation Lead Learning MDM2 gene Malignant Neoplasms Mediating Methodology Modeling Mus Oncogenic Pathway interactions Pharmacology Premalignant Cell Protein p53 Proteins Reagent Regulation Role System TP53 gene Testing Therapeutic Transcriptional Activation cancer cell cell killing drug development experimental study improved in vivo innovation insight metaplastic cell transformation mouse model mutant novel novel strategies novel therapeutics overexpression protein function protein protein interaction public health relevance response treatment strategy tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The oncoproteins Mdm2 and its recently discovered family member Mdmx are frequently overexpressed in many human cancers. Both Mdm2 and Mdmx bind and are direct regulators of the p53 tumor suppressor, but their regulation of p53 activation is only partially understood. Moreover, Mdm2 and Mdmx also have other oncogenic functions that are not well characterized and that likely impact p53 activation and significantly contribute to tumorigenesis. Specifically, altered expression of either Mdm2 or Mdmx can lead to genome instability, which is a hallmark of cancer and facilitator of tumor development; however, the mechanisms for this remain unresolved and appear to have both p53-dependent and p53-independent components. Preliminary data suggest novel mechanisms of Mdm2 and Mdmx in the regulation of p53 and the DNA damage response. Therefore, we hypothesize that alterations in these functions of Mdm2 and Mdmx significantly contribute to their oncogenic activity that leads to genome instability and tumor development. We propose to investigate this hypothesis with three Specific Aims. Experiments in Aim 1 utilize innovative approaches to define the novel functions of Mdm2 and Mdmx that result in genome instability during tumorigenesis and the proteins and pathways required. Experiments in Aim 2 will evaluate a novel mechanism of p53 regulation by Mdm2 and Mdmx with multiple approaches, including a new mouse model. Experiments in Aim 3 will capitalize on the novel functions of Mdm2 and Mdmx in targeting an Achilles' heel in cancer cells, and will identify synthetic lethal combination for cells that have lost a functional Mdm2/Mdmx-p53 pathway. Results from these Aims will reveal critical insights into the oncogenic functions of Mdm2 and Mdmx and their roles in tumorigenesis. Our studies should also open new therapeutic avenues for the treatment of the 50% of human cancers that have inactivated p53.

描述（由申请人提供）：癌蛋白 Mdm2 及其最近发现的家族成员 Mdmx 在许多人类癌症中经常过度表达。 Mdm2 和 Mdmx 均结合 p53 肿瘤抑制因子，并且是 p53 肿瘤抑制因子的直接调节因子，但它们对 p53 激活的调节作用尚不完全清楚。此外，Mdm2 和 Mdmx 还具有其他尚未充分表征的致癌功能，这些功能可能会影响 p53 激活并显着促进肿瘤发生。具体来说，Mdm2 或 Mdmx 表达的改变可能导致基因组不稳定，这是癌症的标志和肿瘤发展的促进因素；然而，其机制仍未解决，并且似乎同时具有 p53 依赖性和 p53 独立成分。初步数据表明 Mdm2 和 Mdmx 在调节 p53 和 DNA 损伤反应中的新机制。因此，我们假设 Mdm2 和 Mdmx 功能的改变显着促进其致癌活性，从而导致基因组不稳定和肿瘤发展。我们建议通过三个具体目标来研究这一假设。目标 1 中的实验利用创新方法来定义 Mdm2 和 Mdmx 的新功能，这些功能导致肿瘤发生过程中的基因组不稳定以及所需的蛋白质和途径。 Aim 2 中的实验将通过多种方法（包括新的小鼠模型）评估 Mdm2 和 Mdmx 调节 p53 的新机制。 Aim 3 中的实验将利用 Mdm2 和 Mdmx 的新功能来靶向癌细胞的致命弱点，并将为失去功能性 Mdm2/Mdmx-p53 通路的细胞识别合成致死组合。这些目标的结果将揭示对 Mdm2 和 Mdmx 的致癌功能及其在肿瘤发生中的作用的重要见解。我们的研究还应该为治疗 50% p53 失活的人类癌症开辟新的治疗途径。