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.
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.
|Zhang, Yun; Xiong, Shunbin; Li, Qin et al. (2014) Tissue-specific and age-dependent effects of global Mdm2 loss. J Pathol 233:380-91|
|Li, Qin; Zhang, Yun; El-Naggar, Adel K et al. (2014) Therapeutic efficacy of p53 restoration in Mdm2-overexpressing tumors. Mol Cancer Res 12:901-11|
|Pant, Vinod; Lozano, Guillermina (2014) Limiting the power of p53 through the ubiquitin proteasome pathway. Genes Dev 28:1739-51|
|Pant, Vinod; Xiong, Shunbin; Jackson, James G et al. (2013) The p53-Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity. Genes Dev 27:1857-67|
|Li, Qin; Lozano, Guillermina (2013) Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy. Clin Cancer Res 19:34-41|
|Post, Sean M; Quintás-Cardama, Alfonso; Pant, Vinod et al. (2010) A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell 18:220-30|
|Barboza, Juan A; Iwakuma, Tomoo; Terzian, Tamara et al. (2008) Mdm2 and Mdm4 loss regulates distinct p53 activities. Mol Cancer Res 6:947-54|
|Valentin-Vega, Y A; Okano, H; Lozano, G (2008) The intestinal epithelium compensates for p53-mediated cell death and guarantees organismal survival. Cell Death Differ 15:1772-81|