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The Journal of Neuroscience, May 15, 2002, 22(10):3898-3909
Transforming Growth Factor- 1 Increases Bad Phosphorylation and
Protects Neurons Against Damage
Yuan
Zhu1,
Guo-Yuan
Yang3,
Barbara
Ahlemeyer1,
Li
Pang3,
Xiao-Ming
Che3,
Carsten
Culmsee1,
Susanne
Klumpp2, and
Josef
Krieglstein1
Institut für 1 Pharmakologie und Toxikologie and
2 Pharmazeutische Chemie, Philipps-Universität,
D-35032 Marburg, Germany, and 3 Department of Surgery,
University of Michigan, Ann Arbor, Michigan 48109
Despite the characterization of neuroprotection by transforming
growth factor- 1 (TGF-1), the signaling pathway mediating its
protective effect is unclear. Bad is a proapoptotic member of the Bcl-2
family and is inactivated on phosphorylation via mitogen-activated
protein kinase (MAPK). This study attempted to address whether MAPK
signaling and Bad phosphorylation were influenced by TGF-1 and,
furthermore, whether these two events were involved in the
antiapoptotic effect of TGF-1. We found a gradual activation of
extracellular signal-regulated kinase 1/2 (Erk1/2) and MAPK-activated
protein kinase-1 (also called Rsk1) and a concomitant increase in Bad
phosphorylation at Ser112 in mouse brains after
adenovirus-mediated TGF-1 transduction under nonischemic and
ischemic conditions induced by transient middle cerebral artery
occlusion. Consistent with these effects, the ischemia-induced increase
in Bad protein level and caspase-3 activation were suppressed in
TGF-1-transduced brain. Consequently, DNA fragmentation, ischemic
lesions, and neurological deficiency were significantly reduced. In
cultured rat hippocampal cells, TGF-1 inhibited the increase in Bad
expression caused by staurosporine. TGF-1 concentration- and
time-dependently activated Erk1/2 and Rsk1 accompanied by an increase
in Bad phosphorylation. These effects were blocked by U0126, a
mitogen-activated protein kinase/Erk kinase 1/2 inhibitor,
suggesting an association between Bad phosphorylation and MAPK
activation. Notably, U0126 and a Rsk1 inhibitor (Ro318220) abolished the neuroprotective activity of TGF-1 in
staurosporine-induced apoptosis, indicating that activation of MAPK is
necessary for the antiapoptotic effect of TGF-1 in cultured
hippocampal cells. Together, we demonstrate that TGF-1 suppresses
Bad expression under lesion conditions, increases Bad phosphorylation,
and activates the MAPK/Erk pathway, which may contribute to its
neuroprotective activity.
Key words:
TGF-1; neuroprotection; MAPK/Erk signaling; Bad
phosphorylation; cerebral ischemia; rat hippocampal cells
Copyright © 2002 Society for Neuroscience 0270-6474/02/22103898-12$05.00/0
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