p53 Regulation Goes Live-Mdm2 and MdmX Co-Star: Lessons Learned from Mouse Modeling

Classically, p53 is considered to be an overarching tumor suppressor gene, important in its role as a transcription factor for a number of genes critical for cell cycle arrest, apoptosis, and senescence. More recently, the scope of p53 function has been further broadened, with evidence emerging that supports essential roles for p53 in reproduction and metabolism. The homologous proteins Mdm2 and MdmX function as the primary negative regulators of p53 stability and activity. Canonically, Mdm2 is thought to regulate p53 through 2 mechanisms: 1) through directly binding the p53 transactivation domain, suppressing p53 activity, and 2) through functioning as an E3 ubiquitin ligase capable of ubiquitinating p53, targeting it for nuclear export and degradation. MdmX similarly functions to bind the p53 transactivation domain; however, it is not characterized to harbor any intrinsic E3 ubiquitin ligase activity. Despite extensive study, the advent of a number of mouse models has brought to light the necessity of studying the p53 pathway at physiological levels and emphasized the major differences that can exist between in vitro and in vivo analysis. While many questions remain, a focus on the use of in vivo models in p53 study is providing a clearer view of how this pathway is regulated, with a newfound emphasis on the role of the Mdm2:MdmX heterodimer, and with that a better understanding of how this pathway could be better manipulated for therapeutic gains.