IN VIVO SIGNIFICANCE OF THE MDM4 AND P73 INTERACTION DURING DEVELOPMENT AND TUMORIGENESIS

The tumor suppressor protein p53 is negatively regulated by Mdm4 protein. The significance of such regulation was determined from mouse models. Mdm4-deficient mice are embryonic lethal at E7.5 in a p53-dependent manner. p73, a member of the p53-family, is a transcription factor with tumor suppressor activity. In vitro studies show that Mdm4 binds to p73 and, further, comprehensive biochemical studies revealed that Mdm4 has higher affinity for p73 than p53. However, little is known about the significance of the Mdm4 and p73 interaction in vivo. This study aimed to elucidate the biological consequences of this interaction during embryogenesis and tumorigenesis using genetic mouse models. My study revealed that p73 loss does not rescue the Mdm4-deficient embryonic lethality, indicating that unrestricted p53 activity leads to the phenotype. Furthermore, loss of p73 does not rescue the runted phenotype of Mdm4∆2/∆2 p53+/− embryos. These findings underscore that unrestricted p53 activity, even at the haploid level, suffices to cause embryonic lethality. Given the prominent roles of Mdm4 and p73 in developing brain, examining the importance of their interaction in this organ was noteworthy. Mdm4-deficiency in the brain causes porencephaly and late gestational embryonic lethality. This phenotype is rescued by deletion of p53. My work depicted that loss of p73 does not rescue the porencephaly phenotype at E14.5. However, interestingly, in the absence of Mdm4, p73 is transcriptionally active and possibly contributes to the vigorous senescent and apoptotic phenotype of p53 in embryonic brain. Since overexpression of Mdm4 and loss of p73 have been implicated in tumor development, I monitored a cohort of mice comprising Mdm4Tg15 p73+/− , Mdm4Tg15, p73+/− and wild type mice. While no survival differences were observed, Mdm4Tg15 p73+/− mice had increased incidence of lymphoma and brain tumors as well as advanced stage lymphoma with extensive dissemination compared to Mdm4Tg15 mice. These observations suggest that increased Mdm4 and p73 haploinsufficiency cooperate in tumorigenesis. Combined, this study suggests that the Mdm4-p73 axis is not as significant as the Mdm4-p53 pathway during embryogenesis and tumor development