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PLoS One. 2010 Jun 30;5(6):e11403. doi: 10.1371/journal.pone.0011403.

Protein-protein interaction antagonists as novel inhibitors of non-canonical polyubiquitylation.

Author information

1
Department of Cell Biology, Institute for Molecular Biology (IBMB-CSIC), Barcelona, Spain.

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-kappaB 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-kappaB by TNF-alpha 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.

PMID:
20613989
PMCID:
PMC2894972
DOI:
10.1371/journal.pone.0011403
[Indexed for MEDLINE]
Free PMC Article

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