Glycogen synthase kinase 3β regulates GATA4 in cardiac myocytes

Inactivation of glycogen synthase kinase 3 beta (GSK3 beta) is critical for transcription of atrial natriuretic factor (ANF) by beta -adrenergic receptors in cardiac myocytes. We examined the mechanism by which GSK3 beta regulates ANF transcription. Stimulation of beta -adrenergic receptors induced nuclear accumulation of GATA4, whereas beta -adrenergic ANF transcription was suppressed by dominant negative GATA4, suggesting that GATA4 plays an important role in beta -adrenergic ANF transcription. Interestingly, GATA4-mediated transcription was markedly attenuated by GSK3 beta. GSK3 beta physically associates with GATA4 and phosphorylates GATA4 in vitro. Overexpression of GSK3 beta suppressed both basal and beta -adrenergic increases in nuclear expression of GATA4, whereas inhibition of GSK3 beta by LiCl caused nuclear accumulation of GATA4, suggesting that GSK3 beta negatively regulates nuclear expression of GATA4. The nuclear exportin Crm1 reduced nuclear expression of GATA4, and the reduction was enhanced by GSK3 beta but not by kinase-inactive GSK3 beta. Leptomycin B, an inhibitor for Crm1, increased basal nuclear GATA4 and suppressed GSK3 beta -induced decreases in nuclear GATA4. These results suggest that GSK3 beta negatively regulates nuclear expression of GATA4 by stimulating Crm1-dependent nuclear export. Inhibition of GSK3 beta by beta -adrenergic stimulation abrogates GSK3 beta -induced nuclear export of GATA4, causing nuclear accumulation of GATA4, which may represent an important signaling mechanism mediating cardiac hypertrophy.