p66Shc Links α 1 -Adrenergic Receptors to a Reactive Oxygen Species-Dependent AKT-FOXO3A Phosphorylation Pathway in Cardiomyocytes
Copyright policy )p66Shc Links α 1 -Adrenergic Receptors to a Reactive Oxygen Species-Dependent AKT-FOXO3A Phosphorylation Pathway in Cardiomyocytes
p66Shc is an adapter protein that is induced by hypertrophic stimuli and has been implicated as a major regulator of reactive oxygen species (ROS) production and cardiovascular oxidative stress responses. This study implicates p66Shc in an α 1 -adrenergtic receptor (α 1 -AR) pathway that requires the cooperative effects of protein kinase (PK)Cε and PKCδ and leads to AKT-FOXO3a phosphorylation in cardiomyocytes. α 1 -ARs promote p66Shc-YY 239/240 phosphorylation via a ROS-dependent mechanism that is localized to caveolae and requires epidermal growth factor receptor (EGFR) and PKCε activity. α 1 -ARs also increase p66Shc-S 36 phosphorylation via an EGFR transactivation pathway involving PKCδ. p66Shc links α 1 -ARs to an AKT signaling pathway that selectively phosphorylates/inactivates FOXO transcription factors and downregulates the ROS-scavenging protein manganese superoxide dismutase (MnSOD); the α 1 -AR-p66Shc-dependent pathway involving AKT does not regulate GSK3. Additional studies show that RNA interference-mediated downregulation of endogenous p66Shc leads to the derepression of FOXO3a-regulated genes such as MnSOD, p27Kip1, and BIM-1. p66Shc downregulation also increases proliferating cell nuclear antigen expression and induces cardiomyocyte hypertrophy, suggesting that p66Shc exerts an antihypertrophic action in neonatal cardiomyocytes. The novel α 1 -AR- and ROS-dependent pathway involving p66Shc identified in this study is likely to contribute to cardiomyocyte remodeling and the evolution of heart failure.
- State University of New York at Potsdam United States
- Columbia-Greene Community College United States
- Columbia University United States
- King’s University United States
Antibiotics, Antineoplastic, Forkhead Box Protein O3, Apoptosis, Cardiomegaly, Forkhead Transcription Factors, Protein Kinase C-epsilon, Cell Enlargement, Caveolae, ErbB Receptors, Glycogen Synthase Kinase 3, Norepinephrine, Oxidative Stress, Protein Kinase C-delta, Animals, Newborn, Doxorubicin, Animals, Myocytes, Cardiac, Phosphorylation, Proto-Oncogene Proteins c-akt, Cells, Cultured
Antibiotics, Antineoplastic, Forkhead Box Protein O3, Apoptosis, Cardiomegaly, Forkhead Transcription Factors, Protein Kinase C-epsilon, Cell Enlargement, Caveolae, ErbB Receptors, Glycogen Synthase Kinase 3, Norepinephrine, Oxidative Stress, Protein Kinase C-delta, Animals, Newborn, Doxorubicin, Animals, Myocytes, Cardiac, Phosphorylation, Proto-Oncogene Proteins c-akt, Cells, Cultured
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