Regulation of p53 by E3s

SIMPLE SUMMARY: The p53 protein is a transcription factor that initiates cell cycle arrest and apoptosis and by this counteracts tumorigenesis. Because of its anti-proliferative activity, p53 levels are usually low as the protein is rapidly degraded, unless its anti-tumoral activity is required. E3s play an important role in this process. While at earlier times only E3s that target p53 for degradation had been identified, more recent years showed that E3s also control p53 localization and its activity, even independently of its degradation. In addition, more and more E3s that target p53 have been identified in the last years. With this review, we want to provide an overview about the E3s that target p53 and how they control p53 abundance and activity. ABSTRACT: More than 40 years of research on p53 have given us tremendous knowledge about this protein. Today we know that p53 plays a role in different biological processes such as proliferation, invasion, pluripotency, metabolism, cell cycle control, ROS (reactive oxygen species) production, apoptosis, inflammation and autophagy. In the nucleus, p53 functions as a bona-fide transcription factor which activates and represses transcription of a number of target genes. In the cytoplasm, p53 can interact with proteins of the apoptotic machinery and by this also induces cell death. Despite being so important for the fate of the cell, expression levels of p53 are kept low in unstressed cells and the protein is largely inactive. The reason for the low expression level is that p53 is efficiently degraded by the ubiquitin-proteasome system and the vast inactivity of the tumor suppressor protein under normal growth conditions is due to the absence of activating and the presence of inactivating posttranslational modifications. E3s are important enzymes for these processes as they decorate p53 with ubiquitin and small ubiquitin-like proteins and by this control p53 degradation, stability and its subcellular localization. In this review, we provide an overview about E3s that target p53 and discuss the connection between p53, E3s and tumorigenesis.