Prostaglandins antagonistically control Bax activation during apoptosis.
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 E(2) (PGE(2)) or its derivative PGA(2) 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. PGD(2) inhibits PGE(2) binding to Bax and PGE(2)-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 PGE(2). This process is distinct, yet cooperative, from that involving the BH3-only protein Bid. Our results establish that the PGE(2)/PGD(2) balance is involved in a new early mechanism of control in the activation of Bax during apoptosis.
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INSERM U 892, Equipe Labellisée Ligue contre le Cancer, 8 Quai Moncousu, Nantes Cedex 01, France.
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Olivier
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D015230:Prostaglandin D2 / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000378:metabolism*
D051023:BH3 Interacting Domain Death Agonist Protein; D011453:Prostaglandins; D051028:bcl-2-Associated X Protein; D015232:Dinoprostone; D003545:Cysteine; D015230:Prostaglandin D2