title: Regulation of E2F1-induced apoptosis by poly(ADP-ribosyl)ation.
abstract: The transcription factor adenovirus E2 promoter-binding factor (E2F)-1 normally enhances cell-cycle progression, but it also induces apoptosis under certain conditions, including DNA damage and serum deprivation. Although DNA damage facilitates the phosphorylation and stabilization of E2F1 to trigger apoptosis, how serum starvation renders cells vulnerable to E2F1-induced apoptosis remains unclear. Because poly(ADP-ribose) polymerase 1 (PARP1), a nuclear enzyme essential for genomic stability and chromatin remodeling, interacts directly with E2F1, we investigated the effects of PARP1 on E2F1-mediated functions in the presence and absence of serum. PARP1 attenuation, which increased E2F1 transactivation, induced G2/M cell-cycle arrest under normal growth conditions, but enhanced E2F1-induced apoptosis in serum-starved cells. Interestingly, basal PARP1 activity was sufficient to modify E2F1 by poly(ADP-ribosyl)ation, which stabilized the interaction between E2F1 and the BIN1 tumor suppressor in the nucleus. Accordingly, BIN1 acted as an RB1-independent E2F1 corepressor. Because E2F1 directly activates the BIN1 gene promoter, BIN1 curbed E2F1 activity through a negative-feedback mechanism. Conversely, when the BIN1-E2F1 interaction was abolished by PARP1 suppression, E2F1 continuously increased BIN1 levels. This is functionally germane, as PARP1-depletion-associated G2/M arrest was reversed by the transfection of BIN1 siRNA. Moreover, PARP-inhibitor-associated anti-transformation activity was compromised by the coexpression of dominant-negative BIN1. Because serum starvation massively reduced the E2F1 poly(ADP-ribosyl)ation, we conclude that the release of BIN1 from hypo-poly(ADP-ribosyl)ated E2F1 is a mechanism by which serum starvation promotes E2F1-induced apoptosis.
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University Cancer Center, Augusta, GA 30912, USA [2] Molecular Signaling Program, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kumari
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University Cancer Center, Augusta, GA 30912, USA [2] Laboratory of Molecular Biology, Research Center for Environmental Genomics, Kobe University, Kobe 657, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Iwasaki
authors.affiliation: Molecular Signaling Program, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pyndiah
authors.affiliation: Molecular Signaling Program, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Cassimere
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University Cancer Center, Augusta, GA 30912, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Palani
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University Cancer Center, Augusta, GA 30912, USA [2] Molecular Signaling Program, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: D
authors.initials: D
authors.lastname: Sakamuro
mesh_terms: D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002460:Cell Line; D004249:DNA Damage; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; C109221:Bin1 protein, mouse; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D000244:Adenosine Diphosphate; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases