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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

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22103898-12$05.00/0

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