Differential roles of glycogen synthase kinase-3 isoforms in the regulation of transcriptional activation.
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.
Liang
Min-Huei
MH
Molecular Neurobiology Section, National Institute of Mental Health, Bethesda, Maryland 20892-1363, USA.
Chuang
De-Maw
DM
D000818:Animals; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D005799:Genes, Dominant; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms; D051381:Rats; D015533:Transcriptional Activation
D020033:Protein Isoforms; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha