title: A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes.
abstract: As a master transcription factor in cellular responses to external stress, tumor suppressor p53 is tightly regulated. Excessive p53 activity during myocardial ischemia causes irreversible cellular injury and cardiomyocyte death. p53 activation is dependent on lysine acetylation by the lysine acetyltransferase and transcriptional coactivator CREB-binding protein (CBP) and on acetylation-directed CBP recruitment for p53 target gene expression. Here, we report a small molecule ischemin, developed with a structure-guided approach to inhibit the acetyl-lysine binding activity of the bromodomain of CBP. We show that ischemin alters post-translational modifications on p53 and histones, inhibits p53 interaction with CBP and transcriptional activity in cells, and prevents apoptosis in ischemic cardiomyocytes. Our study suggests small molecule modulation of acetylation-mediated interactions in gene transcription as a new approach to therapeutic interventions of human disorders such as myocardial ischemia.
authors.affiliation: Department of Structural and Chemical Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Jagat C
authors.initials: JC
authors.lastname: Borah
authors.forename: Shiraz
authors.initials: S
authors.lastname: Mujtaba
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karakikes
authors.forename: Lei
authors.initials: L
authors.lastname: Zeng
authors.forename: Michaela
authors.initials: M
authors.lastname: Muller
authors.forename: Jigneshkumar
authors.initials: J
authors.lastname: Patel
authors.forename: Natasha
authors.initials: N
authors.lastname: Moshkina
authors.forename: Keita
authors.initials: K
authors.lastname: Morohashi
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.forename: Guillermo
authors.initials: G
authors.lastname: Gerona-Navarro
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001391:Azo Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects; D004249:DNA Damage; D055808:Drug Discovery; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D001391:Azo Compounds; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D050882:CREB-Binding Protein; C009850:azobenzene