© 2000 American Heart Association, Inc.
Cellular Biology |
Regulation of Protein Kinase B and 4E-BP1 by Oxidative Stress in Cardiac Myocytes
From the Division of Biomedical Sciences (Molecular Pathology) (F.H.P., A.C.) and National Heart and Lung Institute Division (Cardiac Medicine) (P.H.S.), Imperial College School of Medicine, London, UK.
Correspondence to Angela Clerk, PhD, Division of Biomedical Sciences (Molecular Pathology), Imperial College School of Medicine, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, UK. E-mail a.clerk{at}ic.ac.uk
Abstract—Stimulation of phosphatidylinositol 3'-kinase (PI3K) and protein kinase B (PKB) is implicated in the regulation of protein synthesis in various cells. One mechanism involves PI3K/PKB-dependent phosphorylation of 4E-BP1, which dissociates from eIF4E, allowing initiation of translation from the 7-methylGTP cap of mRNAs. We examined the effects of insulin and H2O2 on this pathway in neonatal cardiac myocytes. Cardiac myocyte protein synthesis was increased by insulin, but was inhibited by H2O2. PI3K inhibitors attenuated basal levels of protein synthesis and inhibited the insulin-induced increase in protein synthesis. Insulin or H2O2 increased the phosphorylation (activation) of PKB through PI3K, but, whereas insulin induced a sustained response, the response to H2O2 was transient. 4E-BP1 was phosphorylated in unstimulated cells, and 4E-BP1 phosphorylation was increased by insulin. H2O2 stimulated dephosphorylation of 4E-BP1 by increasing protein phosphatase (PP1/PP2A) activity. This increased the association of 4E-BP1 with eIF4E, consistent with H2O2 inhibition of protein synthesis. The effects of H2O2 were sufficient to override the stimulation of protein synthesis and 4E-BP1 phosphorylation induced by insulin. These results indicate that PI3K and PKB are important regulators of protein synthesis in cardiac myocytes, but other factors, including phosphatase activity, modulate the overall response.
Key Words: protein synthesis • 4E-BP1 • protein kinase B • oxidative stress • cardiac myocytes
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