Gene regulation downstream of glycogen synthase kinase-3 in neonatal rat ventricular myocytes and T98G cells

Abstract

Glycogen synthase kinase-3 (GSK-3) is a regulatory kinase involved in many important mammalian cell functions. The PI 3-kinase/Akt pathway, which is a major regulator of cell growth and survival in proliferating cells, directly inhibits GSK-3. Inhibition of the PI 3-kinase pathway induces expression of cell cycle arrest and pro-apoptotic genes. Some ofthese genes are induced downstream ofGSK-3 signaling. In this study we show that some genes induced following PI 3-kinase inhibition are regulated by transcription factors that are direct targets of GSK-3 regulation. In doing so, we have identified a transcriptional network downstream of GSK-3 signaling that regulates a subset of genes induced by PI 3-kinase inhibition in proliferating cells. In contrast, GSK-3 plays a much different role in cardiomyocytes, a terminally differentiated cell type. GSK-3 activity is known to inhibit the onset of cardiac hypertrophy in cardiomyocytes. When treated with phenylephrine, a hypertrophy inducing agent, cardiomyocytes experience an up-regulation of 131 unique genes as part of the hypertrophic response. Our studies show that direct inhibition of GSK-3 alone is sufficient to significantly up-regulate a subset of genes induced in the hypertrophic response of cardiomyocytes. Furthermore,we show that the transcription factor CREB, which is targeted by GSK-3 , binds and activates genes induced by direct GSK-3 inhibition.