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- and Fas-mediated
apoptosis through NK-
B activation
Department of Medicine and Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599
To determine the
role of phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear
factor-
B (NF-B) in protecting hepatocytes from tumor necrosis
factor-
(TNF-)- and Fas-mediated apoptosis, we pretreated
primary cultures of mouse hepatocytes with pharmacological and
adenovirus-mediated inhibitors of the PI3K/Akt and NF-B pathways followed by treatment with TNF- or Jo2, an anti-Fas antibody. Jo2
and, to a lesser extent, TNF- phosphorylate Akt. The PI3K inhibitor
LY-294002 blocks TNF-- and Fas-mediated Akt phosphorylation. LY-294002 pretreatment reduces NF-B binding activity and
transcriptional activity and NF-B-responsive gene expression by
TNF- or Jo2. LY-294002 promotes apoptosis after TNF- or
Jo2. The expression of dominant-negative Akt blocks NF-B activation
and sensitizes hepatocytes to TNF-- and Fas-mediated
apoptosis. The expression of constitutively active Akt rescues
LY-294002-pretreated cells from TNF-- and Fas-mediated
apoptosis. Active Akt induces NF-B transcriptional activity
but not NF-B binding activity or IB degradation. Furthermore,
LY-294002 pretreatment blocks TNF-- and Jo2-induced Bcl-xL levels in
hepatocytes, with no effect on the phosphorylation levels of Bad.
Bcl-xL overexpression protects hepatocytes from Fas- but not
TNF--induced apoptosis after sensitization by actinomycin D
or the IB superrepressor. Together, the PI3K/Akt pathway has a
protective role in Fas-mediated apoptosis, which requires
NF-B activation, partially through the subsequent induction of
Bcl-xL.
Bcl-xL; phosphatidylinositol 3-kinase; IB kinase; transcription; signaling
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