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Transforming growth factor-beta 1 increases bad phosphorylation and protects neurons against damage.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2002 May 15; Vol. 22 (10), pp. 3898-909. - Publication Year :
- 2002
-
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.
- Subjects :
- Animals
Apoptosis drug effects
Apoptosis physiology
Caspase 3
Caspases metabolism
Cells, Cultured
Enzyme Activation drug effects
Enzyme Inhibitors pharmacology
Gene Expression drug effects
Hippocampus cytology
Hippocampus drug effects
Hippocampus 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
Phosphorylation drug effects
Ribosomal Protein S6 Kinases metabolism
Signal Transduction drug effects
Signal Transduction physiology
Transduction, Genetic
Transforming Growth Factor beta genetics
Transforming Growth Factor beta1
bcl-Associated Death Protein
Carrier Proteins metabolism
Neurons drug effects
Neurons metabolism
Neuroprotective Agents pharmacology
Ribosomal Protein S6 Kinases, 90-kDa
Transforming Growth Factor beta pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 22
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 12019309
- Full Text :
- https://doi.org/20026373