Glycogen synthase kinase 3 beta 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 recep tors in cardiac myocytes. We examined the mechanism by which GSK3 beta regu lates ANF transcription. Stimulation of beta -adrenergic receptors induced nuclear accumulation of GATA4, whereas beta -adrenergic ANF transcription w as suppressed by dominant negative GATA4, suggesting that GATA4 plays an im portant role in beta -adrenergic ANF transcription. Interestingly, GATA4-me diated transcription was markedly attenuated by GSK3 beta. GSK3 beta physic ally associates with GATA4 and phosphorylates GATA4 in vitro. Overexpressio n of GSK3 beta suppressed both basal and beta -adrenergic increases in nucl ear expression of GATA4, whereas inhibition of GSK3 beta by LiCl caused nuc lear accumulation of GATA4, suggesting that GSK3 beta negatively regulates nuclear expression of GATA4. The nuclear exportin Crm1 reduced nuclear expr ession of GATA4, and the reduction was enhanced by GSK3 beta but not by kin ase-inactive GSK3 beta. Leptomycin B, an inhibitor for Crm1, increased basa l nuclear GATA4 and suppressed GSK3 beta -induced decreases in nuclear GATA 4. These results suggest that GSK3 beta negatively regulates nuclear expres sion of GATA4 by stimulating Crm1-dependent nuclear export. Inhibition of G SK3 beta by beta -adrenergic stimulation abrogates GSK3 beta -induced nucle ar export of GATA4, causing nuclear accumulation of GATA4, which may repres ent an important signaling mechanism mediating cardiac hypertrophy.