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Oxidant-Mediated cAMP Response Element Binding Protein Activation

Calcium Regulation and Role in Apoptosis of Lung Epithelial Cells

Departments of Pharmacology and Pathology, University of Vermont, Burlington, Vermont

Correspondence and requests for reprints should be addressed to Karen M. Lounsbury, University of Vermont, Department of Pharmacology, 89 Beaumont Avenue, Burlington, VT 05405. E-mail: Karen.Lounsbury{at}uvm.edu

Oxidant stress–mediated regulation of extracellular signal-regulated kinases (ERK1/2) is linked to pathologic outcomes in lung epithelium, yet a role for Ca²⁺ and Ca²⁺/cAMP-response element binding protein (CREB) in ERK1/2 signaling has not been defined. In this study, we tested the hypotheses that oxidants induce Ca²⁺-mediated phosphorylation of ERK and CREB, and that CREB is required for oxidant-induced proliferation and apoptosis. H₂O₂ initiated an influx of extracellular Ca²⁺Ca²⁺Ca²⁺Ca²⁺ that was required for phosphorylation of both ERK and CREB in C10 lung epithelial cells. H₂O₂-mediated CREB phosphorylation was sensitive to MEK inhibition, suggesting that crosstalk between Ca²⁺, ERK, and CREB signaling pathways contributes to the oxidant-induced response. Reduction of CREB activity, using a dominant-negative CREB construct, inhibited c-fos steady-state mRNA levels, but unexpectedly enhanced bcl-2 steady-state mRNA levels after H₂O₂ exposure. Whereas inhibition of CREB activity had no detectable effect on H₂O₂ stimulation of cell cycle, loss of CREB activity significantly reduced the number of cells undergoing apoptosis. These data support a novel communication between Ca²⁺-ERK1/2 and CREB elicited by H₂O₂, and further provide evidence that CREB is an important regulator of apoptosis in oxidant-mediated responses of lung epithelial cells.

Key Words: calcium signaling • lung pathology • mitogen-activated protein kinase • reactive oxygen species

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