Glycogen synthase kinase 3beta-mediated apoptosis of primary cortical astrocytes involves inhibition of nuclear factor kappaB signaling.
Recent studies have revealed a positive correlation between astrocyte apoptosis and rapid disease progression in persons with neurodegenerative diseases. Glycogen synthase kinase 3beta (GSK-3beta) is a molecular regulator of cell fate in the central nervous system and a target of the phosphatidylinositol 3-kinase (PI-3K) pathway. We have therefore examined the ... role of the PI-3K pathway, and of GSK-3beta, in regulating astrocyte survival. Our studies indicate that inhibition of PI-3K leads to apoptosis in primary cortical astrocytes. Furthermore, overexpression of a constitutively active GSK-3beta mutant (S9A) is sufficient to cause astrocyte apoptosis, whereas an enzymatically inactive GSK-3beta mutant (K85M) has no effect. In light of reports on the interplay between GSK-3beta and nuclear factor kappaB (NF-kappaB), and because of the antiapoptotic activity of NF-kappaB, we examined the effect of GSK-3beta overexpression on NF-kappaB activation. These experiments revealed strong inhibition of NF-kappaB activation in astrocytes upon overexpression of the S9A, but not the K85M, mutant of GSK-3beta. This was accompanied by stabilization of the NF-kappaB-inhibitory protein, IkappaBalpha and down-regulation of IkappaB kinase (IKK) activity. These findings therefore implicate GSK-3beta as a regulator of NF-kappaB activation in astrocytes and suggest that the pro-apoptotic effects of GSK-3beta may be mediated at least in part through the inhibition of NF-kappaB pathway.
Mesh Terms:
Adenoviridae, Animals, Apoptosis, Astrocytes, Cells, Cultured, Cyclooxygenase 2, DNA, DNA, Complementary, Enzyme Activation, Enzyme Inhibitors, Glutathione Transferase, Glycogen Synthase Kinase 3, I-kappa B Kinase, Immunoblotting, In Situ Nick-End Labeling, Isoenzymes, Luciferases, Mitogen-Activated Protein Kinases, Mutation, NF-kappa B, Phosphatidylinositol 3-Kinases, Precipitin Tests, Prostaglandin-Endoperoxide Synthases, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Rats, Rats, Sprague-Dawley, Signal Transduction, Time Factors, Transcription, Genetic
Adenoviridae, Animals, Apoptosis, Astrocytes, Cells, Cultured, Cyclooxygenase 2, DNA, DNA, Complementary, Enzyme Activation, Enzyme Inhibitors, Glutathione Transferase, Glycogen Synthase Kinase 3, I-kappa B Kinase, Immunoblotting, In Situ Nick-End Labeling, Isoenzymes, Luciferases, Mitogen-Activated Protein Kinases, Mutation, NF-kappa B, Phosphatidylinositol 3-Kinases, Precipitin Tests, Prostaglandin-Endoperoxide Synthases, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Rats, Rats, Sprague-Dawley, Signal Transduction, Time Factors, Transcription, Genetic
Mol. Cell. Biol.
Date: Jul. 01, 2003
PubMed ID: 12808104
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