Abstract
The Bax protein (Bcl-2-associated X protein) is pivotal for the apoptotic process. Bax, which resides in an inactive form in the cytosol of healthy cells, is activated during the early stages of apoptosis and becomes associated with mitochondria through poorly understood mechanisms. In this study, we show that a family of bioactive lipids, namely prostaglandins, regulates Bax-dependent apoptosis. The prostaglandin E2 (PGE2) or its derivative PGA2 binds to Bax, induces its change of conformation, and thereby triggers apoptosis. A cysteine present in the loop between the two transmembrane α-helices of Bax, Cys126 is critical for its activation. PGD2 inhibits PGE2 binding to Bax and PGE2-induced apoptosis, as well as cell death induced by staurosporine and UV-B in various cell lines. This result is consistent with the fact that apoptosis is accompanied during these treatments by an increase in PGE2. This process is distinct, yet cooperative, from that involving the BH3-only protein Bid. Our results establish that the PGE2/PGD2 balance is involved in a new early mechanism of control in the activation of Bax during apoptosis.
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Abbreviations
- Bax:
-
Bcl-2-associated X protein
- COX-2:
-
cyclooxygenase 2
- L-PGDS:
-
lipocalin-like prostaglandin D2 synthase
- mPGES-1:
-
microsomal prostaglandin E2 synthase 1
- PGE2:
-
prostaglandin E2
- 15-keto PGE2:
-
15-keto prostaglandin E2
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Acknowledgements
This work was supported by a special grant from the Ligue contre le Cancer (Equipe labellisée Ligue). We thank Dr. J Grassi (CEA/Saclay, France) for the gift of AChE-coupled PGE2 and recombinant AChE and Gaëlle Blanchet (Service de Biochimie, Faculté de Medecine de Nantes, France) for technical assistance.
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Lisenn Lalier performed the in vitro experiments and drafted the manuscript. Pierre Francois Cartron performed the acellular studies, Christophe Olivier performed some of the microinjection experiments, Gwenola Bougras carried out the phenotyping characterization of the cell lines and Lisa Oliver the immunohistochemical characterization and confocal studies. Cedric Logé and Jean-Michel Robert participated in the molecular modeling of PGE2/Bax interaction. Francois M Vallette conceived of the study and wrote the final version of the manuscript.
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Lalier, L., Cartron, PF., Olivier, C. et al. Prostaglandins antagonistically control Bax activation during apoptosis. Cell Death Differ 18, 528–537 (2011). https://doi.org/10.1038/cdd.2010.128
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DOI: https://doi.org/10.1038/cdd.2010.128
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