title: A Chemical Inhibitor of the Skp2/p300 Interaction that Promotes p53-Mediated Apoptosis.
abstract: Skp2 is thought to have two critical roles in tumorigenesis. As part of the SCF(Skp2) ubiquitin ligase, Skp2 drives the cell cycle by mediating the degradation of cell cycle proteins. Besides the proteolytic activity, Skp2 also blocks p53-mediated apoptosis by outcompeting p53 for binding p300. Herein, we exploit the Skp2/p300 interaction as a new target for Skp2 inhibition. An affinity-based high-throughput screen of a combinatorial cyclic peptoid library identified an inhibitor that binds to Skp2 and interferes with the Skp2/p300 interaction. We show that antagonism of the Skp2/p300 interaction by the inhibitor leads to p300-mediated p53 acetylation, resulting in p53-mediated apoptosis in cancer cells, without affecting Skp2 proteolytic activity. Our results suggest that inhibition of the Skp2/p300 interaction has a great potential as a new anticancer strategy, and our Skp2 inhibitor can be developed as a chemical probe to delineate Skp2 non-proteolytic function in tumorigenesis.
authors.affiliation: Departments of Chemistry and Advanced Material Science, Pohang University of Science and Technology (POSTECH), Pohang 37673 (Republic of Korea).|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 (USA).
authors.forename: Misook
authors.initials: M
authors.lastname: Oh
authors.affiliation: New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation, Daegu 41061 (Republic of Korea).
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Departments of Chemistry and Advanced Material Science, Pohang University of Science and Technology (POSTECH), Pohang 37673 (Republic of Korea).
authors.forename: Heejo
authors.initials: H
authors.lastname: Moon
authors.affiliation: Departments of Chemistry and Advanced Material Science, Pohang University of Science and Technology (POSTECH), Pohang 37673 (Republic of Korea).
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Hyun
authors.affiliation: Departments of Chemistry and Advanced Material Science, Pohang University of Science and Technology (POSTECH), Pohang 37673 (Republic of Korea). hslim@postech.ac.kr.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 (USA). hslim@postech.ac.kr.
authors.forename: Hyun-Suk
authors.initials: HS
authors.lastname: Lim
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D011485:Protein Binding; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D044786:S-Phase Kinase-Associated Proteins; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors
keywords: Skp2; cancer; inhibitors; p300; protein-protein interactions