The c-MYC-interacting proapoptotic tumor suppressor BIN1 is a transcriptional target for E2F1 in response to DNA damage.
The E2F1 transcription factor, which was originally identified as a cell-cycle initiator, mediates apoptosis in response to DNA damage. As E2F1-induced apoptosis is an attractive mechanism for cancer therapy, it is critical to fully elucidate its effector pathways. Here, we show that the c-MYC-interacting proapoptotic tumor suppressor, BIN1, is transcriptionally activated by E2F1 and mediates E2F1-induced apoptosis in response to DNA damage. Acting through the DNA-binding and transactivation domains, ectopically expressed E2F1 activated the human BIN1 promoter, which contains canonical E2F-recognition sites. Conversely, depletion of E2F1 by small interfering RNA or germline deletion led to BIN1 deficiency. DNA-damaging agents (which included etoposide) increased BIN1 levels, unless E2F1 was deficient. Moreover, endogenous E2F1 protein interacted directly with the BIN1 gene promoter in chromatin, particularly after etoposide treatment. Notably, suppression of BIN1 expression using an antisense (AS) technique attenuated the cell death mediated by E2F1 and etoposide. Although the p53 tumor suppressor, its sibling protein p73, and caspases are well-known E2F1 effectors for DNA damage-induced apoptosis, AS-BIN1 did not compromise their apoptotic functions. Our results collectively suggest that BIN1 is a novel transcriptional target of E2F1 that triggers a unique mode of cell death in response to DNA damage.
Cassimere
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Division of Cancer Biology, Department of Pathology, School of Medicine and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
Pyndiah
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Sakamuro
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D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D004249:DNA Damage; D050687:E2F1 Transcription Factor / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
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; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins