ERK1/2 regulates two sequential steps promoting monocyte survival to peroxynitrite

• Published in: Journal of cellular physiology Vol. 210; no. 1; pp. 177 - 182
• Main Authors: Cerioni, L., Cantoni, O.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-01-2007
• Subjects: Arachidonate 5-Lipoxygenase - metabolism; Arachidonic Acid - metabolism; Arachidonic Acid - pharmacology; bcl-2-Associated X Protein - metabolism; bcl-Associated Death Protein - metabolism; Cell Survival - drug effects; Cyclosporine - pharmacology; Cytochromes c - metabolism; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Humans; Hydroxyeicosatetraenoic Acids - metabolism; Hydroxyeicosatetraenoic Acids - pharmacology; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins - drug effects; Mitochondrial Membrane Transport Proteins - metabolism; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - metabolism; Monocytes - drug effects; Monocytes - metabolism; Peroxynitrous Acid - pharmacology; Phospholipases A - antagonists & inhibitors; Phospholipases A - metabolism; Phosphorylation; Protein Kinase C-alpha - metabolism; Protein Transport - drug effects; U937 Cells
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.20837

Previous studies from our laboratory indicate that cytosolic phospholipase A2 (cPLA2)‐released arachidonic acid promotes monocyte/macrophage survival in the presence of peroxynitrite. In particular, the lipid messenger is metabolised by 5‐lipoxygenase (5‐LO) to 5‐hydroxyeicosatetraenoic acid and causes the mitochondrial translocation of protein kinase Cα (PKCα), an event associated with the cytosolic accumulation of Bad and Bax. Here we show that phosphorylation reactions driven by extracellular regulated kinase 1/2 (ERK1/2) critically regulate the activation/nuclear translocation of 5‐LO. Inhibition of ERK1/2 was invariably associated with the cytosolic localisation of PKCα, the mitochondrial accumulation of Bad and Bax and with a rapid mitochondrial permeability transition‐dependent necrosis. All these events were prevented by nanomolar concentrations of 5‐hydroxyeicosatetraenoic acid. Hence, in addition to the previously characterised effects on cPLA2, ERK1/2 critically regulates 5‐LO activity in the absence of additional downstream targets in the survival signalling preventing peroxynitrite toxicity. J. Cell. Physiol. 210: 177–182, 2007. © 2006 Wiley‐Liss, Inc.