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Title: | Protein-protein interaction antagonists as novel inhibitors of non-canonical polyubiquitylation |
Authors: | Scheper, Johanna ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
Keywords: | Polyubiquitylation Lysine |
Issue Date: | 30-Jun-2010 |
Publisher: | Public Library of Science |
Citation: | PLoS ONE 5(6): e11403 (2010) |
Abstract: | [Background]: Several pathways that control cell survival under stress, namely RNF8-dependent DNA damage recognition and repair, PCNA-dependent DNA damage tolerance and activation of NF-kB by extrinsic signals, are regulated by the tagging of key proteins with lysine 63-based polyubiquitylated chains, catalyzed by the conserved ubiquitin conjugating heterodimeric enzyme Ubc13-Uev. [Methodology/Principal Findings]: By applying a selection based on in vivo protein-protein interaction assays of compounds from a combinatorial chemical library followed by virtual screening, we have developed small molecules that efficiently antagonize the Ubc13-Uev1 protein-protein interaction, inhibiting the enzymatic activity of the heterodimer. In mammalian cells, they inhibit lysine 63-type polyubiquitylation of PCNA, inhibit activation of NF-kB by TNF-a and sensitize tumor cells to chemotherapeutic agents. One of these compounds significantly inhibited invasiveness, clonogenicity and tumor growth of prostate cancer cells. [Conclusions/Significance]: This is the first development of pharmacological inhibitors of non-canonical polyubiquitylation that show that these compounds produce selective biological effects with potential therapeutic applications. |
Publisher version (URL): | http://dx.doi.org/10.1371/journal.pone.0011403 |
URI: | http://hdl.handle.net/10261/33998 |
DOI: | http://dx.doi.org/10.1371/journal.pone.0011403 |
ISSN: | 1932-6203 |
Appears in Collections: | (CBM) Artículos (CIC) Artículos (IQAC) Artículos (IBMB) Artículos |
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