Novel oncogenic functions of Mdm2 and Mdmx

描述（由申请人提供）：肿瘤蛋白Mdm2及其最近发现的家族成员Mdmx在许多人类癌症中经常过表达。Mdm2和Mdmx都是p53肿瘤抑制因子的直接调节因子，但它们对p53激活的调节仅部分了解。此外，Mdm2和Mdmx还具有其他未被很好地描述的致癌功能，这些功能可能影响p53的激活并显著促进肿瘤的发生。具体来说，Mdm2或Mdmx的表达改变可导致基因组不稳定，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，似乎有p53依赖和p53独立的成分。初步数据提示Mdm2和Mdmx调控p53和DNA损伤反应的新机制。因此，我们假设Mdm2和Mdmx这些功能的改变显著促进了它们的致癌活性，从而导致基因组不稳定和肿瘤的发展。我们建议从三个具体目标来研究这一假设。Aim 1的实验利用创新的方法来定义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的实验将通过多种方法评估Mdm2和Mdmx调控p53的新机制，包括一种新的小鼠模型。Aim 3的实验将利用Mdm2和Mdmx的新功能来靶向癌细胞的致命弱点，并将确定对失去功能Mdm2/Mdmx-p53通路的细胞的合成致死组合。这些目标的结果将揭示Mdm2和Mdmx的致癌功能及其在肿瘤发生中的作用。我们的研究还应该为治疗50%的p53失活的人类癌症开辟新的治疗途径。

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.