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J Biol Chem, Vol. 273, Issue 46, 30713-30718, November 13, 1998

Protein Kinase C  (PKC) Inhibits the Expression of Glutamine Synthetase in Glial Cells via the PKC Regulatory Domain and Its Tyrosine Phosphorylation

Chaya Brodie^§, Krisztina Bogi, Peter Acs, Patricia S. Lorenzo, Lindsey Baskin, and Peter M. Blumberg

From the  Molecular Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, NCI, National Institutes of Health, Bethesda, Maryland 20892 and the ^§ Department of Life-Sciences, Bar-Ilan University, Ramat-Gan, Israel 52900

Protein kinase C (PKC) plays an important role in the proliferation and differentiation of glial cells. In a recent study we found that overexpression of PKC reduced the expression of the astrocytic marker glutamine synthetase (GS). In this study we explored the mechanisms involved in the inhibitory effect of PKC on the expression of glutamine synthetase. Using PKC chimeras we first examined the role of the catalytic and regulatory domains of PKC on the expression of glutamine synthetase. We found that cells stably transfected with chimeras between the regulatory domain of PKC and the catalytic domains of PKC or  inhibited the expression of GS, similar to the inhibition exerted by overexpression of PKC itself. In contrast, no significant effects were observed in cells transfected with the reciprocal PKC chimeras between the regulatory domains of PKC or  and the catalytic domain of PKC. PKC has been shown to undergo tyrosine phosphorylation in response to various activators. Tyrosine phosphorylation of PKC in response to phorbol 12-myristate 13-acetate and platelet-derived growth factor occurred only in chimeras which contained the PKC regulatory domain. Cells transfected with a PKC mutant (PKC5), in which the five putative tyrosine phosphorylation sites were mutated to phenylalanine, showed markedly diminished tyrosine phosphorylation in response to phorbol 12-myristate 13-acetate and platelet-derived growth factor and normal levels of GS. Our results indicate that the regulatory domain of PKC mediates the inhibitory effect of this isoform on the expression of GS. Phosphorylation of PKC on tyrosine residues in the regulatory domain is implicated in this inhibitory effect.

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Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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