p53-independent function of Mdmx in tumorigenesis

描述（由申请人提供）：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更深入的了解，将有助于开发新的治疗方法来提高患者的生存率。该项目将研究一种特定的癌蛋白Mdmx，即Mdm 2家族成员，及其在淋巴瘤发展中的作用。Mdmx经常在人类癌症中过度表达，包括淋巴瘤。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。虽然也已经表明Mdmx具有p53独立的功能，但这些功能尚未完全理解。最近，Mdmx被证明是重要的DNA损伤反应介导的DNA损伤信号从γ射线和癌基因。当DNA受损时，修复途径被诱导以确保适当的修复，从而保护基因组稳定性并抑制肿瘤发展。我们的初步数据揭示了Mdmx的p53和Mdm 2独立功能，并提供了重要的洞察Mdmx在维持基因组稳定性和淋巴瘤发生的潜在新机制。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，我们提出了两个具体目标。目的1将描述Mdmx功能的p53非依赖性机制，因为它涉及DNA损伤信号传导和修复。目的2将集中于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/Mdm 2独立功能的理解。我们的研究还将提供知识，以开发新的治疗淋巴瘤和其他过度表达Mdmx的癌症。这些目标将通过范德比尔特大学的研究生教育强化教学培训计划来实现，范德比尔特大学是国家癌症研究所指定的综合癌症中心。范德比尔特拥有数百个研究实验室，为学员提供广泛的培训，合作机会，并接触到各个领域的专家。研究生培训计划允许参加研讨会，课程和研讨会。作为一个实习生在慕尼黑实验室，有机会受益于小鼠模型，肿瘤抑制途径，染色体稳定性和B细胞淋巴瘤的专业知识，并参与许多合作。强调导师和学员之间的一对一指导和互动，这对研究生培训的成功非常有价值。研究生培训计划和本研究计划的结合将推动这名学员成为一名独立的科学研究人员。

DESCRIPTION (provided by applicant): 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.