Glycogen Synthase Kinase 3β Regulates GATA4 in Cardiac Myocytes

Abstract

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

GSK-3β inhibition protects mesothelial cells during experimental peritoneal dialysis through upregulation of the heat shock response

“…The role of GSK-3β as a potential drug target has become more and more prominent in the last years (Phukan et al 2010). Several studies reported that inhibition of GSK-3β by selective small molecules is protective in clinically relevant disease models: GSK-3β inhibition was shown to improve insulin resistance in type II diabetes (Gum et al 2003;Ring et al 2003), to have beneficial effects in neurological disorders like Alzheimer's disease (Hsiung et al 2003) and to reduce cardiac hypertrophy and ischaemia (Morisco et al 2001). Despite increasing evidence for the therapeutic potential of GSK-3β inhibition to counteract various cytotoxic stressors, to our knowledge, there are no studies investigating GSK-3β inhibition in the model of experimental PD.…”

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

“…We too have demonstrated that DOX interferes with GATA-4 DNA binding but also that CO restores cardiac GATA-4 activity, alone as well as after DOX, thereby connecting it directly to the GATA-4 antiatrophic effect. Akt1 positively regulates GATA-4 transactivation in cardiomyocytes via phosphorylation and inactivation of GSK3β (28), and here DOX reduces pGSK3β, a negative regulator of GATA-4 in the nucleus. CO increases GSK3β phosphorylation and thereby functionally inactivates GSK3β.…”

“…This result strongly implicates Akt1, via Bad phosphorylation, in the protection against DOXinduced apoptosis by CO. And because Akt1 negatively regulates GSK3β activation, and GSK3β negatively regulates nuclear GATA-4 (26), GSK3β is implicated in the low GATA binding levels. CO increases phospho-GSK3β levels, decreasing GSK3β activation, a known factor in GATA-4 transcriptional activation (28).…”

Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4

“…GATA-4 actions involve combinatorial interactions with other cell-restricted or inducible transcription factors, including Nkx2.5, Mef2, SRF, nuclear factor of activated T cells, SMAD, and c-fos (reviewed in reference 73). GATA-4 activity is also directly modulated by signaling cascades; ERK and p38 MAPK phosphorylate and enhance GATA-4 transcriptional activation domains (15,41), while glycogen synthase kinase (GSK3␤) phosphorylates the GATA-4 DNA binding domain and inhibits nuclear GATA-4 accumu- lation (50). Through its cooperative interaction with other transcriptional regulators, GATA-4 serves as a nuclear integrator of several signaling pathways, most notably calcineurin, MAPK, PI3 kinase, and receptor serine-threonine kinases.…”