The p53 tumor suppressor pathway is a complex network of signals that fluctuate to regulate cell proliferation and death. Mdm2 and Mdm4 are crucial inhibitors of p53 and are often present at high levels in tumors thus dampening p53 activity eliminating the need for p53 mutations. Mdm2 also has p53-independent functions that promote chromosomal instability. Biochemical data indicated that Mdm2 and Mdm4 also bind p73, a p53 related protein. We have identified physiologically important interactions of Mdm2 with p73 in vivo. Thus, our overarching hypothesis is that the oncogenic functions of the Mdm proteins are a combined effect of inhibiting p53 and p73 functions. Furthermore, because normal cells, unlike tumor cells, do not tolerate high levels of Mdm2, we also hypothesize that tumor-specific changes alter cell physiology to tolerate high Mdm2 levels. To test these hypotheses, we will decipher the intricate relationship between p73 and Mdm2 by studying the phenotype of Mdm2-/-p73-/- mice. In addition, we will cross tumor prone Mdm2 transgenic and SNP309 mice (with higher than normal Mdm2 levels) with p73 mice to examine effects of concomitant p73 loss on chromosomal aberrations and tumor phenotypes.
In aim 2, we will determine the physiological relevance of the Mdm4/p73 interactions, and we will generate p73 heterozygous Mdm4 transgenic mice to examine the importance of this combination on a tumor phenotype. Lastly, we will identify factors that allow tumor (but not normal) cells to tolerate high Mdm2 levels using genetic screens.

Public Health Relevance

We have identified physiologically relevant interactions between the tumor suppressor and p53-related protein, p73, and an inhibitor Mdm2. These studies will define new functional relationships and components of the p53 tumor suppressor pathway, thus expanding the number of possible drug targets for therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047296-25
Application #
8400415
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Watson, Joanna M
Project Start
1988-07-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
25
Fiscal Year
2013
Total Cost
$234,605
Indirect Cost
$86,121
Name
University of Texas MD Anderson Cancer Center
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Ortiz, Guadalupe J; Lozano, Guillermina (2018) SNPing away at mutant p53 activities. Genes Dev 32:195-196
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Aryal, Neeraj K; Wasylishen, Amanda R; Pant, Vinod et al. (2017) Loss of digestive organ expansion factor (Diexf) reveals an essential role during murine embryonic development that is independent of p53. Oncotarget 8:103996-104006
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Tashakori, Mehrnoosh; Zhang, Yun; Xiong, Shunbin et al. (2016) p53 Activity Dominates That of p73 upon Mdm4 Loss in Development and Tumorigenesis. Mol Cancer Res 14:56-65

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