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J Biol Chem, Vol. 274, Issue 14, 9200-9206, April 2, 1999
B-independent Decreases in Nuclear
Factor B Activation in Human Lung Adenocarcinoma (A549) Cells
From the Division of Pharmacology and Toxicology, College of
Pharmacy, University of Texas, Austin, Texas 78712
Acrolein is a highly electrophilic
,
-unsaturated aldehyde to which humans are exposed in various
situations. In the present study, the effects of sublethal doses of
acrolein on nuclear factor 
B (NF-B) activation in A549 human lung
adenocarcinoma cells were investigated. Immediately following a 30-min
exposure to 45 fmol of acrolein/cell, glutathione (GSH) and DNA
synthesis and NF-B binding were reduced by more than 80%. All
parameters returned to normal or supranormal levels by 8 h
post-treatment. Pretreatment with acrolein completely blocked
12-O-tetradecanoylphorbol-13-acetate (TPA)-induced
activation of NF-B. Cells treated for 1 h with 1 mM
diethyl maleate (DEM) showed a 34 and 53% decrease in GSH and DNA
synthesis, respectively. DEM also reduced NF-B activation by 64% at
2 h post-treatment, with recovery to within 22% of control at
8 h. Both acrolein and DEM decreased NF-B function ~50% at 2 h after treatment with TPA, as shown by a secreted alkaline phosphatase reporter assay. GSH returned to control levels by 8 h
after DEM treatment, but proliferation remained significantly depressed
for 24 h. Interestingly, DEM caused a profound decrease in NF-B
binding, even at doses as low as 0.125 mM that had little effect on GSH. Neither acrolein nor DEM had any effect on the levels of
phosphorylated or nonphosphorylated inhibitor B- (IB-). Furthermore, acrolein decreased NF-B activation in cells depleted of
IB- by TPA stimulation in the presence of cycloheximide, demonstrating that the decrease in NF-B activation was not the result of increased binding by the inhibitory protein. This conclusion was further supported by the finding that acrolein modified NF-B in
the cytosol prior to chemical dissociation from IB with detergent. Together, these data support the conclusion that the inhibition of
NF-B activation by acrolein and DEM is IB-independent. The mechanism appears to be related to direct modification of thiol groups
in the NF-B subunits.
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