Transforming growth factor-beta 1 increases bad phosphorylation and protects neurons against damage.

Abstract

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.

• Authors: Yuan Zhu, Guo-Yuan Yang, Barbara Ahlemeyer, Li Pang, Xiao-Ming Che, Carsten Culmsee, Susanne Klumpp, Josef Krieglstein
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 22 Issue 10 Pg. 3898-909 (May 15 2002) ISSN: 1529-2401 [Electronic] United States
• PMID: 12019309 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Bad protein, mouse
• Carrier Proteins
• Enzyme Inhibitors
• Neuroprotective Agents
• TGFB1 protein, human
• Tgfb1 protein, mouse
• Tgfb1 protein, rat
• Transforming Growth Factor beta
• Transforming Growth Factor beta1
• bcl-Associated Death Protein
• Ribosomal Protein S6 Kinases
• Ribosomal Protein S6 Kinases, 90-kDa
• Rps6ka1 protein, mouse
• Rps6ka1 protein, rat
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• CASP3 protein, human
• Casp3 protein, mouse
• Casp3 protein, rat
• Caspase 3
• Caspases

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Carrier Proteins (metabolism)
• Caspase 3
• Caspases (metabolism)
• Cells, Cultured
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Gene Expression (drug effects)
• Hippocampus (cytology, drug effects, metabolism)
• Infarction, Middle Cerebral Artery (metabolism)
• Ischemic Attack, Transient (metabolism)
• Male
• Mice
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases (metabolism)
• Neurons (cytology, drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• Phosphorylation (drug effects)
• Ribosomal Protein S6 Kinases (metabolism)
• Ribosomal Protein S6 Kinases, 90-kDa
• Signal Transduction (drug effects, physiology)
• Transduction, Genetic
• Transforming Growth Factor beta (genetics, pharmacology)
• Transforming Growth Factor beta1
• bcl-Associated Death Protein