Published ahead of print on September 8, 2005, doi:10.1165/rcmb.2005-0153OC Am. J. Respir. Cell Mol. Biol., Volume 34, Number 1, January 2006, 7-14 A more recent version of this article appeared on January 1, 2006
Submitted on April 25, 2005 Oxidant-mediated CREB Activation: Calcium Regulation and Role in Apoptosis of Lung Epithelial CellsChristy A Barlow1,1 Department of Pharmacology, University of Vermont, Burlington, VT, USA, 2 Department of Pathology, University of Vermont, Burlington, VT, USA * To whom correspondence should be addressed. 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+ 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 following 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.
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