Studies that employ targeted inactivation of genes coding for specific ubiquitin system enzymes and substrates in animals can provide a more systematic view into the broad spectrum of pathologies that may result from aberrations in ubiquitin-mediated proteolysis. Better understanding of the processes and identification of the components involved in the degradation of key regulatory proteins will lead to the development Inhibitors,research,lifescience,medical of mechanism-based drugs that

will target specifically only the involved proteins. While the first drug, a specific proteasome inhibitor, is already on the Inhibitors,research,lifescience,medical market,80 it appears that one important hallmark of the new era we are entering now will be the discovery of novel drugs based on targeting of specific processes such as inhibiting aberrant Mdm2- or E6-AP-mediated accelerated targeting of the tumor suppressor p53 which will lead to regain of its lost function. Figure

7 Some of the different functions of modification by ubiquitin and ubiquitin-like proteins. Inhibitors,research,lifescience,medical Figure 8 Aberrations in the ubiquitin-proteasome system and pathogenesis of human diseases. Many reviews have been published on different aspects of the ubiquitin system. The purpose of this article is to bring to the reader several milestones along the historical pathway which led to the discovery Inhibitors,research,lifescience,medical of the ubiquitin system. For additional reading on the ubiquitin system, the reader is referred to numerous review articles written on the subject (for some older reviews, see for example Glickman Inhibitors,research,lifescience,medical et al.81 and Pickart et al.82). Some parts of this review, including several figures, are based on buy OTX015 another published review article.83

Acknowledgments Research in the laboratory of Aaron Ciechanover is supported by grants from the Dr Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), the Israel Science Foundation (ISF), Resveratrol the German-Israeli Foundation (GIF) for Scientific Research and Development, an Israel Cancer Research Fund (ICRF) USA Professorship, the Deutsche-Israeli Cooperation Program (DIP), and the Rubicon European Union (EU) Network of Excellence. Published with permission of the Nobel Foundation©. This article is based on the Nobel Lecture delivered in Stockholm on December 8, 2004, and published in: Ciechanover, A. (2005). Les Prix Nobel. The Nobel Foundation, Stockholm, Sweden. pp.