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(Received for publication, February 1, 1996, and in revised form, April 2, 1996)
From the Treatment of L929 cells with tumor necrosis
factor
Volume 271, Number 24,
Issue of June 14, 1996
pp. 14560-14566
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
-Mediated Apoptosis Requires Ras and the Activation of
Mitogen-activated Protein Kinase
and¶
Division of Basic Sciences, National Jewish
Center for Immunology and Respiratory Medicine, Denver, Colorado 80206 and the ¶ Department of Pharmacology, University of Colorado
Medical School, Denver, Colorado 80262
(TNF) activates a programmed cell death pathway resulting
in apoptosis. We investigated the intracellular signaling pathways
activated in L929 cells by TNF. TNF robustly activates Jun kinase
(JNK), a member of the mitogen-activated protein kinase (MAPK) family.
In addition, p42MAPK is activated, but a 10-fold greater
concentration of TNF was required for substantial MAPK activation
than was needed for maximal JNK stimulation. Simultaneous treatment of
L929 cells with fibroblast growth factor (FGF-2) significantly reduced
the apoptotic response to TNF. FGF-2 substantially activated the
Raf/MEK/MAPK (where MEK is mitogen-activated protein kinase kinase)
pathway but did not affect TNF activation of JNK. These results
indicate that although JNK may play an important role in transmitting
the TNF signal from the cell surface to the nucleus, activation of
the JNK pathway is not sufficient to induce apoptosis. Expression of
dominant-negative Asn-17 Ras in L929 cells diminished the FGF-2
stimulation of p42MAPK and eliminated the protective effect
of FGF-2. Asn-17 Ras expression did not affect JNK activity and had no
effect on TNF activation of JNK. Pharmacological inhibition of MEK-1
activity by incubation of cells with the compound PD 098059 blocked
p42MAPK activation and FGF-2 protection against apoptosis.
Interestingly, activated Val-12 Ras expression substantially enhanced
TNF-mediated apoptosis in L929 cells, but Val-12 Ras did not
constitutively activate MAPK in L929 cells and FGF-2 partially
protected Val-12 Ras-expressing cells from TNF-mediated apoptosis.
Our data indicate that activation of the MAPK pathway mediates an FGF-2
protective effect against apoptosis and highlights the important role
that integration of multiple intracellular signaling pathways plays in
the regulation of cell growth and death.
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