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      Drug discovery in the ubiquitin-proteasome system.

      Nature reviews. Drug discovery

      metabolism, Ubiquitins, chemistry, antagonists & inhibitors, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, physiopathology, drug therapy, Neurodegenerative Diseases, Neoplasms, Humans, Drug Design, Animals

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          Abstract

          Regulated protein turnover via the ubiquitin-proteasome system (UPS) underlies a wide variety of signalling pathways, from cell-cycle control and transcription to development. Recent evidence that pharmacological inhibition of the proteasome can be efficacious in the treatment of human cancers has set the stage for attempts to selectively inhibit the activities of disease-specific components of the UPS. Here, we review recent advances linking UPS components with specific human diseases, most prominently cancer and neurodegenerative disorders, and emphasize potential sites of therapeutic intervention along the regulated protein-degradation pathway.

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          Live or let die: the cell's response to p53.

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            A genomic and functional inventory of deubiquitinating enzymes.

            Posttranslational modification of proteins by the small molecule ubiquitin is a key regulatory event, and the enzymes catalyzing these modifications have been the focus of many studies. Deubiquitinating enzymes, which mediate the removal and processing of ubiquitin, may be functionally as important but are less well understood. Here, we present an inventory of the deubiquitinating enzymes encoded in the human genome. In addition, we review the literature concerning these enzymes, with particular emphasis on their function, specificity, and the regulation of their activity.
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              Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53.

              The tumor suppressor p53 is degraded by the ubiquitin-proteasome system. p53 was polyubiquitinated in the presence of E1, UbcH5 as E2 and MDM2 oncoprotein. A ubiquitin molecule bound MDM2 through sulfhydroxy bond which is characteristic of ubiquitin ligase (E3)-ubiquitin binding. The cysteine residue in the carboxyl terminus of MDM2 was essential for the activity. These data suggest that the MDM2 protein, which is induced by p53, functions as a ubiquitin ligase, E3, in human papillomavirus-uninfected cells which do not have E6 protein.
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                Author and article information

                Journal
                10.1038/nrd2056
                16816840

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