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.

Public Health Relevance

The oncogenic functions of Mdm2 and Mdmx, which are frequently overexpressed in many human cancers, are incompletely understood. This proposal will investigate novel functions of Mdm2 and Mdmx that contribute to genome instability and malignant tumor formation. Results from the proposed studies will increase understanding of Mdm2 and Mdmx in tumor development, and will lead to the identification of potentially targetable pathways and proteins for the treatment of human malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA181204-03
Application #
9232880
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Johnson, Ronald L
Project Start
2014-07-18
Project End
2019-05-31
Budget Start
2016-02-01
Budget End
2016-05-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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Feeley, Kyle P; Adams, Clare M; Mitra, Ramkrishna et al. (2017) Mdm2 Is Required for Survival and Growth of p53-Deficient Cancer Cells. Cancer Res 77:3823-3833
Eischen, Christine M (2016) Role of Mdm2 and Mdmx in DNA repair. J Mol Cell Biol :
Eischen, Christine M (2016) Genome Stability Requires p53. Cold Spring Harb Perspect Med 6:
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
Tonsing-Carter, Eva; Bailey, Barbara J; Saadatzadeh, M Reza et al. (2015) Potentiation of Carboplatin-Mediated DNA Damage by the Mdm2 Modulator Nutlin-3a in a Humanized Orthotopic Breast-to-Lung Metastatic Model. Mol Cancer Ther 14:2850-63