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.
There is currently a 50% survival rate for patients diagnosed with a common blood cancer called non- Hodgkin's lymphoma. Our studies will provide important insight into how lymphomas develop, which will allow for the possibility of new treatment options to be developed for the thousands of people with non-Hodgkin's lymphoma.
|Carrillo, A M; Bouska, A; Arrate, M P et al. (2015) Mdmx promotes genomic instability independent of p53 and Mdm2. Oncogene 34:846-56|
|Carrillo, Alexia M; Hicks, Mellissa; Khabele, Dineo et al. (2015) Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells. Mol Cancer Res 13:1197-205|
|Melo, Alexia N; Eischen, Christine M (2012) Protecting the genome from mdm2 and mdmx. Genes Cancer 3:283-90|