The p53 protein is an important tumor suppressor that acts as a key regulator of the integrity of the genome. Two essential regulators of the p53 protein are Mdm2 and its homologue Mdmx. Like Mdm2,... Show moreThe p53 protein is an important tumor suppressor that acts as a key regulator of the integrity of the genome. Two essential regulators of the p53 protein are Mdm2 and its homologue Mdmx. Like Mdm2, Mdmx represses p53-induced transcription. However, Mdmx cannot ubiquitinate or degrade p53 opposed to Mdm2. In chapter 2, studies aimed to better understand the functional differences between Mdmx and Mdm2. By generation of hybrid constructs between Mdmx and Mdm2, we found that in addition to a complete RING domain of Mdm2, also an internal acidic domain is required for p53 ubiquitination and degradation. In chapter 3 the role of Mdmx in human tumor formation is described. The results show that the mdmx gene can function as an oncogene and demonstrate that the transforming function of the Mdmx protein is dependent on its ability to interact with p53. In chapter 4, the regulation of Mdmx stability is described. We demonstrate that the stability of Mdmx is determined by a balance in de-ubiquitination by HAUSP and ubiquitination by Mdm2. Chapter 5 the results of initial studies on the role of SUMO conjugation in Mdmx function are shown. Show less
