Mdm2 and Mdm4 control distinct p53 functions that cooperate in suppression of tumorigenesis

Cells have safeguard mechanisms to prevent uncontrolled proliferation and progression to malignant disease in response to DNA damage. A key mediator in these processes is the tumor suppressor, p53, whose indispensable role in preventing tumorigenesis is validated by its frequent mutation in human cancers. p53 activates transcription of various target genes, resulting in a cell cycle arrest or apoptosis of damaged cells. The p53 protein in normal cells is negatively regulated by the Mdm2 and Mdm4 oncoproteins. Here I show that loss of Mdm4 results in a p53-dependent cell cycle arrest and confirm that loss of Mdm2 causes p53-dependent apoptosis. While Mdm2 is known to catalyze p53 degradation, my data demonstrate that Mdm4 protects p53 from Mdm2 degradation. In addition, loss of Mdm2 or Mdm4 results in transcriptional activation of distinct p53 target genes correlating with induction of cell cycle arrest or apoptosis. To address the role of these vital p53 functions in tumor suppression, I utilized a mouse tumor model with an abrogated p53-dependent apoptotic pathway. Additional deletion of p21 in these mice abolishes p53 cell cycle control. Most importantly, loss of p21 and apoptosis accelerated tumor onset as compared to mice lacking either p21 or apoptosis, revealing an essential cooperative relationship between these two facets of p53 function. In addition, my findings illustrate that p21 couples cell cycle control with preservation of genomic stability, defining the mechanism of p53 cell cycle control in suppression of tumorigenesis