TY - JOUR
T1 - The c-MYC-interacting proapoptotic tumor suppressor BIN1 is a transcriptional target for E2F1 in response to DNA damage
AU - Cassimere, E. K.
AU - Pyndiah, S.
AU - Sakamuro, D.
N1 - Funding Information:
Acknowledgements. We thank Dr. K Helin, Dr. G Melino, and Dr. L Yamasaki for providing the HA-ER-E2F1 cDNA, the p73b cDNA, and the E2f1 (−/−) MEFs, respectively. We are obliged to members of the Stanley S Scott Cancer Center clerical offices for assistance in the preparation of the article. This work was supported in part by grants from the US Army Department of Defense Prostate Cancer Research Program (DAMD 17-02-1-0131), the Walther Cancer Foundation, the Wendy Will Case Cancer Fund, the Susan G Komen Breast Cancer Foundation, and the Louisiana Cancer Research Consortium Awards (to DS). EKC was the recipient of the Bowen Minority Fellowship, the Purdue Doctoral Fellowship, and the Ruth L Kirschstein National Research Service Awards for Individual Predoctoral Fellows (NIH F31).
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
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U2 - 10.1038/cdd.2009.98
DO - 10.1038/cdd.2009.98
M3 - Article
C2 - 19629135
AN - SCOPUS:70449707449
SN - 1350-9047
VL - 16
SP - 1641
EP - 1653
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 12
ER -