Abstract
14-3-3 proteins are dimeric phophoserine-binding molecules that participate in important cellular processes such as cell proliferation, cell-cycle control and the stress response. In this work, we report that several isoforms of 14-3-3s are expressed in neonatal rat cardiomyocytes. To understand their function, we utilized a general 14-3-3 peptide inhibitor, R18, to disrupt 14-3-3 functions in cardiomyocytes. Cardiomyocytes infected with adenovirus-expressing YFP-R18 (AdR18) exhibited markedly increased protein synthesis and atrial natriuretic peptide production and potentiated the responses to norepinephrine stimulation. This response was blocked by the pretreatment with LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor. Consistent with a role of PI3K in the R18 effect, R18 induced phosphorylation of a protein cloned from the vakt oncogene of retrovirus AKT8 (Akt - also called protein kinase B, PKB) at Ser473 and glycogen synthase 3beta (GSK3beta) at Ser9, but not extracellular signal-regulated kinase 1/2 (ERK1/2). AdR18-induced PKB and GSK3beta phosphorylation was completely blocked by LY294002. In addition, a member of the nuclear factor of activated T cells (NFAT) family, NFAT3, was converted into faster mobility forms and translocated into the nucleus upon the treatment of AdR18. These results suggest that 14-3-3s inhibits cardiomyocytes hypertrophy through regulation of the PI3K/PKB/GSK3beta and NFAT pathway.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
14-3-3 Proteins / antagonists & inhibitors
-
14-3-3 Proteins / metabolism*
-
Active Transport, Cell Nucleus
-
Animals
-
Animals, Newborn
-
Atrial Natriuretic Factor / metabolism
-
Cardiomegaly / enzymology
-
Cardiomegaly / metabolism*
-
Cardiomegaly / pathology*
-
Cell Nucleus / metabolism
-
Cells, Cultured
-
DNA-Binding Proteins / chemistry
-
DNA-Binding Proteins / metabolism
-
Glycogen Synthase Kinase 3 / metabolism*
-
Glycogen Synthase Kinase 3 beta
-
Models, Biological
-
Myocytes, Cardiac / enzymology
-
Myocytes, Cardiac / metabolism*
-
Myocytes, Cardiac / pathology*
-
NFATC Transcription Factors
-
Nuclear Proteins / chemistry
-
Nuclear Proteins / metabolism
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphoinositide-3 Kinase Inhibitors
-
Phosphorylation
-
Protein Biosynthesis
-
Protein Isoforms / antagonists & inhibitors
-
Protein Isoforms / metabolism
-
Protein Serine-Threonine Kinases / metabolism
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins c-akt
-
Rats
-
Rats, Sprague-Dawley
-
Transcription Factors / chemistry
-
Transcription Factors / metabolism
Substances
-
14-3-3 Proteins
-
DNA-Binding Proteins
-
NFATC Transcription Factors
-
Nuclear Proteins
-
Phosphoinositide-3 Kinase Inhibitors
-
Protein Isoforms
-
Proto-Oncogene Proteins
-
Transcription Factors
-
Atrial Natriuretic Factor
-
Akt1 protein, rat
-
Glycogen Synthase Kinase 3 beta
-
Gsk3b protein, rat
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt
-
Glycogen Synthase Kinase 3