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Differential Roles of Glycogen Synthase Kinase-3 Isoforms in the Regulation of Transcriptional Activation

Overview
Journal J Biol Chem
Specialty Biochemistry
Date 2006 Aug 17
PMID 16912034
Citations 73
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Abstract

Glycogen synthase kinase-3 (GSK-3) exists as two structurally similar isoforms, alpha and beta, whose activities are negatively regulated by serine phosphorylation but positively controlled by tyrosine phosphorylation. We used GSK-3 isoform-specific small interfering RNAs, dominant negative mutants, and pharmacological inhibitors to search for the differential roles for both GSK-3 isoforms in regulating transcriptional activation in cultured rat cerebral cortical neurons. GSK-3alpha and GSK-3beta were shown to have differentially regulated transactivation such that GSK-3alpha silencing/inhibition was more robust than GSK-3beta silencing/inhibition in causing cAMP-responsive element- and NF-kappaB-dependent transactivation. Moreover, protein-DNA array studies identified two novel GSK-3-regulated transcription factors, early growth response 1 and Smad3/4, which were oppositely affected by GSK-3alpha or GSK-3beta silencing or inhibition. Taken together, our results underscore critical variations in the function and regulation of GSK-3alpha and GSK-3beta. The development of GSK-3 isoform-specific inhibitors is thus crucial for therapeutic intervention of GSK-3-related neuropathological conditions.

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