title: Resveratrol induces apoptosis by directly targeting Ras-GTPase-activating protein SH3 domain-binding protein 1.
abstract: Resveratrol (trans-3,5,4'-truhydroxystilbene) possesses a strong anticancer activity exhibited as the induction of apoptosis through p53 activation. However, the molecular mechanism and direct target(s) of resveratrol-induced p53 activation remain elusive. Here, the Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) was identified as a potential target of resveratrol, and in vitro binding assay results using resveratrol-conjugated Sepharose 4B beads confirmed their direct binding. Depletion of G3BP1 significantly diminishes resveratrol-induced p53 expression and apoptosis. We also found that G3BP1 negatively regulates p53 expression by interacting with ubiquitin-specific protease 10 (USP10), a deubiquitinating enzyme of p53. Disruption of the interaction of p53 with USP10 by G3BP1 interference leads to the suppression of p53 deubiquitination. Resveratrol, on the other hand, directly binds to G3BP1 and prevents the G3BP1/USP10 interaction, resulting in enhanced USP10-mediated deubiquitination of p53, and consequently increased p53 expression. These findings disclose a novel mechanism of resveratrol-induced p53 activation and resveratrol-induced apoptosis by direct targeting of G3BP1.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: N
authors.initials: N
authors.lastname: Oi
authors.affiliation: 1] Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China [2] Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Yuan
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Malakhova
authors.affiliation: 1] Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China [2] Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China [3] Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: K
authors.initials: K
authors.lastname: Luo
authors.affiliation: 1] Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China [2] Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China [3] Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: 1] Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China [2] Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Lou
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004265:DNA Helicases; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D000075223:Poly-ADP-Ribose Binding Proteins; D011485:Protein Binding; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D000075223:Poly-ADP-Ribose Binding Proteins; D000067776:RNA Recognition Motif Proteins; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; C431363:USP10 protein, human; D043222:Ubiquitin Thiolesterase; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases; D000077185:Resveratrol