Differential roles of glycogen synthase kinase-3 isoforms in the regulation of transcriptional activation

Abstract

Glycogen synthase kinase-3 (GSK-3) exists as two structurally similar isoforms, α and β, 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-3α and GSK-3β were shown to have differentially regulated transactivation such that GSK-3α silencing/inhibition was more robust than GSK-3β silencing/inhibition in causing cAMP-responsive element- and NF-κB-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-3α or GSK-3β silencing or inhibition. Taken together, our results underscore critical variations in the function and regulation of GSK-3α and GSK-3β. The development of GSK-3 isoform-specific inhibitors is thus crucial for therapeutic intervention of GSK-3-related neuropathological conditions.