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.
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Abbreviations
- E2F:
-
adenovirus E2 promoter-binding factor
- PARP1:
-
poly(adenosine diphosphate [ADP]-ribose) polymerase 1
- PAR:
-
poly(ADP-ribose) polymer chain
- BIN1:
-
bridging integrator 1
- BAR:
-
BIN-Amphiphysin-Rvs homology domain
- MBD:
-
MYC-binding domain
- SH3:
-
src homology domain 3
- MB:
-
marked box domain
- TA:
-
transactivation domain
- ER:
-
estrogen receptor
- GST:
-
glutathione-S-transferase
- HA:
-
hemagglutinin
- DAPI:
-
4′,6-diamidino-2-phenylindole
- 4-OHT:
-
4-hydroxy tamoxifen
- sh-/si-RNA:
-
short hairpin-/small interfering-RNA
- ChIP:
-
chromatin immunoprecipitation
- Luc:
-
luciferase-reporter vector
- qRT-PCR:
-
quantitative reverse transcriptase-polymerase chain reaction
- MEFs:
-
mouse embryonic fibroblasts
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Acknowledgements
We thank F Dantzer, M Weitzman, and K Münger for the reagents; W King for technical assistance with flow cytometry; GC Prendergast for helpful discussion; and M Herlyn for critical reading of the manuscript. This work was supported in part by grants from the US National Institutes of Health (NIH) (R01CA140379) and the US Army Department of Defense Prostate Cancer Research Program (DAMD 17-02-1-0131) (to DS). TI was the recipient of the 2013-2014 Kobe University Presidential Award for International Education and Research. EKC was the recipient of the Ruth L. Kirschstein National Research Service Award for Predoctoral Training (NIH F31).
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DS holds a 1999 US Patent with GC Prendergast, no. 6,410,238, ‘Box-dependent Myc-interacting protein (Bin1) compositions and uses thereof’ (The Wistar Institute of Anatomy and Biology, Philadelphia, PA, USA).
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Kumari, A., Iwasaki, T., Pyndiah, S. et al. Regulation of E2F1-induced apoptosis by poly(ADP-ribosyl)ation. Cell Death Differ 22, 311–322 (2015). https://doi.org/10.1038/cdd.2014.146
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DOI: https://doi.org/10.1038/cdd.2014.146
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