Transforming growth factor-β1 increases bad phosphorylation and protects neurons against damage

被引:226
作者
Zhu, Y
Yang, GY
Ahlemeyer, B
Pang, L
Che, XM
Culmsee, C
Klumpp, S
Krieglstein, J
机构
[1] Univ Marburg, Inst Pharmakol & Toxikol, D-35032 Marburg, Germany
[2] Univ Marburg, Inst Pharmazeut Chem, D-35032 Marburg, Germany
[3] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA
关键词
TGF-beta; 1; neuroprotection; MAPK/Erk signaling; Bad phosphorylation; cerebral ischemia; rat hippocampal cells;
D O I
10.1523/JNEUROSCI.22-10-03898.2002
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Despite the characterization of neuroprotection by transforming growth factor-beta1 (TGF-beta1), 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-beta1 and, furthermore, whether these two events were involved in the antiapoptotic effect of TGF-beta1. 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 Ser(112) in mouse brains after adenovirus-mediated TGF-beta1 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-beta1-transduced brain. Consequently, DNA fragmentation, ischemic lesions, and neurological deficiency were significantly reduced. In cultured rat hippocampal cells, TGF-beta1 inhibited the increase in Bad expression caused by staurosporine. TGF-beta1 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-beta1 in staurosporine-induced apoptosis, indicating that activation of MAPK is necessary for the antiapoptotic effect of TGF-beta1 in cultured hippocampal cells. Together, we demonstrate that TGF-beta1 suppresses Bad expression under lesion conditions, increases Bad phosphorylation, and activates the MAPK/Erk pathway, which may contribute to its neuroprotective activity.
引用
收藏
页码:3898 / 3909
页数:12
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