Protein-Protein Interaction Antagonists as Novel Inhibitors of Non-Canonical Polyubiquitylation
Por:
Scheper, J, Guerra-Rebollo, M, Sanclimens, G, Moure, A, Masip, I, Gonzalez-Ruiz, D, Rubio, N, Crosas, B, Meca-Cortes, O, Loukili, N, Plans, V, Morreale, A, Blanco, J, Ortiz, AR, Messeguer, A, Thomson, TM
Publicada:
30 jun 2010
Resumen:
Background: pathways that control cell survival under stress, namely RNF8-dependent DNA damage recognition and repair, PCNA-dependent DNA damage tolerance and activation of NF-kappa B 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-kappa B 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.
Filiaciones:
Scheper, J:
CSIC, IBMB, Inst Mol Biol, Dept Cell Biol, Barcelona, Spain
Guerra-Rebollo, M:
CSIC, IBMB, Inst Mol Biol, Dept Cell Biol, Barcelona, Spain
Sanclimens, G:
CSIC, IQAC, Inst Adv Chem Catalonia, Dept Biol Organ Chem, Barcelona, Spain
Moure, A:
CSIC, IQAC, Inst Adv Chem Catalonia, Dept Biol Organ Chem, Barcelona, Spain
Masip, I:
CSIC, IQAC, Inst Adv Chem Catalonia, Dept Biol Organ Chem, Barcelona, Spain
Gonzalez-Ruiz, D:
CSIC, UAM, CBM, Ctr Biol Mol Severo Ochoa,Bioinformat Unit, Madrid, Spain
Rubio, N:
CSIC, CIC, Catalan Ctr Cardiovasc Res, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed, Barcelona, Spain
Crosas, B:
CSIC, IBMB, Inst Mol Biol, Dept Cell Biol, Barcelona, Spain
Meca-Cortes, O:
CSIC, IBMB, Inst Mol Biol, Dept Cell Biol, Barcelona, Spain
Loukili, N:
CSIC, IBMB, Inst Mol Biol, Dept Cell Biol, Barcelona, Spain
Plans, V:
CSIC, IBMB, Inst Mol Biol, Dept Cell Biol, Barcelona, Spain
Morreale, A:
CSIC, UAM, CBM, Ctr Biol Mol Severo Ochoa,Bioinformat Unit, Madrid, Spain
Blanco, J:
CSIC, CIC, Catalan Ctr Cardiovasc Res, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed, Barcelona, Spain
Ortiz, AR:
CSIC, UAM, CBM, Ctr Biol Mol Severo Ochoa,Bioinformat Unit, Madrid, Spain
Messeguer, A:
CSIC, IQAC, Inst Adv Chem Catalonia, Dept Biol Organ Chem, Barcelona, Spain
Thomson, TM:
CSIC, IBMB, Inst Mol Biol, Dept Cell Biol, Barcelona, Spain
Gold, Green Published
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