p53-independent function of Mdmx in tumorigenesis

目前非霍奇金淋巴瘤的生存率很低。因此，对淋巴瘤发生的分子机制有了更深入的了解，将有助于开发新的治疗方法，以提高患者的生存率。本项目将研究Mdm2家族成员Mdmx的特异性癌蛋白及其在淋巴瘤发展中的作用。Mdmx在包括淋巴瘤在内的人类癌症中经常过度表达。作为肿瘤抑制因子p53的调节因子，Mdmx过表达可通过抑制p53诱导肿瘤发生。尽管也有研究表明Mdmx具有与p53无关的功能，但这些功能尚不完全清楚。最近，Mdmx通过介导来自γ辐射和癌基因的DNA损伤信号被证明在DNA损伤反应中起重要作用。当DNA受损时，修复途径被诱导以确保适当的修复，以保持基因组的稳定性并抑制肿瘤的发展。我们的初步数据揭示了Mdmx独立于p53和Mdm2的功能，并为Mdmx在维持基因组稳定性和淋巴瘤发生中的潜在新机制提供了重要的见解。因此，为了研究Mdmx在基因组不稳定性中的重要性及其对淋巴瘤发展的贡献，我们提出了两个特定目的。目的1将描述与DNA损伤信号传导和修复有关的不依赖于p53的Mdmx功能机制。目的2将关注Mdmx在染色体稳定性和淋巴瘤发展中的作用。这些研究的结果将增加我们对Mdmx及其可能导致癌症的p53/ mdm2独立功能的理解。我们的研究也将为淋巴瘤和其他过表达Mdmx的癌症提供新的治疗方法。这些目标将通过范德比尔特大学研究生教育的密集教学培训项目来实现，范德比尔特大学是国家癌症研究所指定的综合癌症中心。拥有数百个研究实验室，范德比尔特为受训者提供广泛的培训，合作机会，并获得各种领域的专家。研究生培训计划允许参加研讨会、课程和专题讨论会。作为Eischen实验室的实习生，您将有机会从小鼠模型、肿瘤抑制通路、染色体稳定性和B细胞淋巴瘤形成方面的专业知识中获益，并参与许多合作。导师和学员之间强调一对一的指导和互动，这对研究生培训的成功非常有价值。研究生培训计划和这项研究计划的结合将推动该学员成为一名独立的科学研究人员。

Currently survival from non-Hodgkin's lymphoma is poor. Therefore, a greater understanding of the molecular mechanisms involved in lymphomagenesis should result in the development of new treatments to increase survival of patients. This project will investigate a specific oncoprotein, Mdmx, that is an Mdm2 family member, and its role in lymphoma development. Mdmx is frequently overexpressed in human cancers, including lymphoma. As a regulator of the tumor suppressor p53, Mdmx overexpression can induce tumorigenesis through inhibition of p53. Although it has also been shown that Mdmx has p53-independent functions, these are not completely understood. Recently, Mdmx was shown to be important in the DNA damage response by mediating DNA damage signals from gamma irradiation and oncogenes. When DNA is damaged, repair pathways are induced to ensure proper repair to conserve genomic stability and inhibit tumor development. Our preliminary data reveal a p53 and Mdm2 independent function of Mdmx and provide important insight into a potentially novel mechanism for Mdmx in the maintenance of genomic stability and lymphomagenesis. Therefore, to examine the importance of Mdmx in genomic instability and its contribution to lymphoma development, we have proposed two Specific Aims. Aim 1 will characterize the p53- independent mechanism of Mdmx function as it pertains to DNA damage signaling and repair. Aim 2 will focus on the role of Mdmx in chromosome stability and lymphoma development. Results from these investigations will increase our understanding of Mdmx and its p53/Mdm2-independent functions that likely contribute to cancer. Our studies will also provide knowledge to develop new treatments for lymphoma and other cancers that overexpress Mdmx. These goals will be achieved through an intensive didactic training program of graduate education at Vanderbilt University, which is a National Cancer Institute designated comprehensive Cancer Center. With hundreds of research laboratories, Vanderbilt provides trainees with extensive training, collaborative opportunities, and access to experts in a variety of fields. The graduate training program allows engagement in seminars, courses, and symposia. As a trainee in the Eischen laboratory, there is the opportunity to benefit from expertise in mouse models, tumor suppressor pathways, chromosome stability, and B cell lymphomagenesis, and be involved in numerous collaborations. There is emphasis on one-on-one guidance and interaction between the mentor and trainee that is very valuable to the success of graduate training. A combination of the graduate training program and this research proposal will propel this trainee towards becoming an independent scientific researcher.