Growth hormone regulates phosphorylation and function of CCAAT/enhancer-binding protein beta by modulating Akt and glycogen synthase kinase-3.
Growth hormone (GH) regulates transcription factors associated with c-fos, including C/EBPbeta. Two forms of C/EBPbeta, liver-activating protein (LAP) and liver inhibitory protein (LIP), are dephosphorylated in GH-treated 3T3-F442A fibroblasts. GH-induced dephosphorylation of LAP and LIP is reduced when cells are preincubated with phosphatidylinositol 3'-kinase (PI3K) inhibitors. GH activates Akt and ... inhibits glycogen synthase kinase-3 (GSK-3). Lithium, a GSK-3 inhibitor, increases GH-dependent dephosphorylation of LAP and LIP. Both are in vitro substrates of GSK-3, suggesting that GSK-3 inactivation contributes to GH-promoted dephosphorylation of C/EBPbeta. Alkaline phosphatase increases binding of LAP homodimers and decreases binding of LIP homodimers to c-fos, suggesting that dephosphorylation of C/EBPbeta modifies their ability to bind DNA. Both alkaline phosphatase- and GH-mediated dephosphorylation comparably increase binding of endogenous LAP in 3T3-F442A cells. In cells overexpressing LAP and GSK-3, LAP binding decreases, suggesting that GSK-3-mediated phosphorylation interferes with LAP binding. Expression of constitutively active GSK-3 reduced GH-stimulated c-fos promoter activity. These studies indicate that PI3K/Akt/GSK-3 mediates signaling between GH receptor and the nucleus, promoting dephosphorylation of C/EBPbeta. Dephosphorylation increases binding of LAP complexes to the c-fos promoter and may contribute to the participation of C/EBPbeta in GH-stimulated c-fos expression.
Mesh Terms:
3T3 Cells, Alkaline Phosphatase, Animals, CCAAT-Enhancer-Binding Protein-beta, CHO Cells, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Cell Nucleus, Cricetinae, Enzyme Activation, Enzyme Inhibitors, Glycogen Synthase Kinase 3, Glycogen Synthase Kinases, Humans, Immunoblotting, Lithium, Mice, Phosphatidylinositol 3-Kinases, Phosphorylation, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-fos, Signal Transduction, Time Factors, Transcriptional Activation, Transfection
3T3 Cells, Alkaline Phosphatase, Animals, CCAAT-Enhancer-Binding Protein-beta, CHO Cells, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Cell Nucleus, Cricetinae, Enzyme Activation, Enzyme Inhibitors, Glycogen Synthase Kinase 3, Glycogen Synthase Kinases, Humans, Immunoblotting, Lithium, Mice, Phosphatidylinositol 3-Kinases, Phosphorylation, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-fos, Signal Transduction, Time Factors, Transcriptional Activation, Transfection
J. Biol. Chem.
Date: Jun. 01, 2001
PubMed ID: 11278638
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