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Molecular and Cellular Biology, July 2003, p. 4649-4662, Vol. 23, No. 13
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.13.4649-4662.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Glycogen Synthase Kinase 3ß-Mediated Apoptosis of Primary Cortical Astrocytes Involves Inhibition of Nuclear Factor B Signaling

Program in Genetics, Department of Biochemistry and Biophysics,¹ Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York²

Received 11 February 2003/ Accepted 25 March 2003

Recent studies have revealed a positive correlation between astrocyte apoptosis and rapid disease progression in persons with neurodegenerative diseases. Glycogen synthase kinase 3ß (GSK-3ß) 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-3ß, 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-3ß mutant (S9A) is sufficient to cause astrocyte apoptosis, whereas an enzymatically inactive GSK-3ß mutant (K85M) has no effect. In light of reports on the interplay between GSK-3ß and nuclear factor B (NF-B), and because of the antiapoptotic activity of NF-B, we examined the effect of GSK-3ß overexpression on NF-B activation. These experiments revealed strong inhibition of NF-B activation in astrocytes upon overexpression of the S9A, but not the K85M, mutant of GSK-3ß. This was accompanied by stabilization of the NF-B-inhibitory protein, IB and down-regulation of IB kinase (IKK) activity. These findings therefore implicate GSK-3ß as a regulator of NF-B activation in astrocytes and suggest that the pro-apoptotic effects of GSK-3ß may be mediated at least in part through the inhibition of NF-B pathway.

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