Abstract
The enzymatic activity of phospholipase D (PLD) is known to be essential for cell survival and protection from apoptosis. However, the mechanisms regulating PLD activity during apoptosis remain unknown. Here we report that cleavage of PLD1 by caspases facilitates p53-mediated apoptosis. Cleavage of PLD1 into an N-terminal fragment (NF-PLD1) and a C-terminal fragment at the amino-acid sequence, DDVD545, led to a reduction in PLD1 activity. However, a caspase-resistant mutant form of PLD1 retained significant levels of enzymatic activity and apoptotic function as compared to wild-type PLD1. Exogenous NF-PLD1 expression induced apoptosis through a dominant-negative effect on the activity of endogenous PLD1. During apoptosis, a small fraction of PLD1 is cleaved by caspases in a p53-independent manner and NF-PLD1 amplifies apoptotic signaling through inhibition of the remaining PLD1 activity. As PLD1 suppresses the ATM–Chk2–p53 pathway, elimination of PLD1 activity through NF-PLD1 or si-RNA against PLD1 increases apoptosis in a p53-dependent manner. Taken together, our results reveal that cleavage of PLD1 by caspases promotes apoptosis via modulation of the p53-dependent cell death pathway.
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Abbreviations
- CF-PLD1:
-
C-terminal fragment of PLD1
- Chk2:
-
check point kinase-2
- MDM2:
-
mouse double minute gene number 2
- NF-PLD1:
-
N-terminal fragment of PLD1
- PA:
-
phosphatidic acid
- PARP:
-
poly(ADP-ribose) polymerase
- PC:
-
phosphatidylcholine
- PLD:
-
phospholipase D
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Acknowledgements
This study was supported by a grant (no. R01-2006-000-10521-0; 2006) from the Basic Research Program of the Korea Science & Engineering Foundation References.
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Jang, Y., Namkoong, S., Kim, Y. et al. Cleavage of phospholipase D1 by caspase promotes apoptosis via modulation of the p53-dependent cell death pathway. Cell Death Differ 15, 1782–1793 (2008). https://doi.org/10.1038/cdd.2008.111
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DOI: https://doi.org/10.1038/cdd.2008.111
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