p53-independent function of Mdmx in tumorigenesis

目前，非霍奇金淋巴瘤的存活率很低。因此，更好地了解淋巴肿大的分子机制应该会导致开发新的治疗方法来提高患者的存活率。这个项目将研究一种特定的癌蛋白MDMX，它是MDM2家族的成员，以及它在淋巴瘤发生中的作用。MDMX在包括淋巴瘤在内的人类癌症中经常过度表达。MDMX作为抑癌基因P53的调控因子，其过表达可通过抑制P53而诱导肿瘤发生。尽管已经证明MDMX具有不依赖于P53的功能，但这些功能还没有完全被理解。最近，MDMX被证明在DNA损伤反应中起重要作用，它介导了来自伽玛射线和癌基因的DNA损伤信号。当DNA受损时，会诱导修复途径，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的P53和MDM2独立的功能，并为MDMX在维持基因组稳定和淋巴瘤发生中潜在的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的目标。目的1将描述MDMX功能的p53非依赖性机制，因为它与DNA损伤信号和修复有关。目标2将集中于MDMX在染色体稳定和淋巴瘤发生中的作用。这些研究的结果将增加我们对MDMX及其与p53/MDM2无关的功能的理解，这些功能可能与癌症有关。我们的研究还将为开发治疗淋巴瘤和其他过度表达MDMX的癌症的新疗法提供知识。这些目标将通过范德比尔特大学研究生教育的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性癌症中心。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、合作机会和接触各种领域的专家。研究生培训计划允许参加研讨会、课程和座谈会。作为Eischen实验室的实习生，有机会从小鼠模型、肿瘤抑制途径、染色体稳定性和B细胞淋巴瘤发生方面的专业知识中受益，并参与了许多合作。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。研究生培训计划和这项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。

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.