Abstract
Growth hormone (GH), which is reduced with age, corrects the impaired proliferative capacity of livers of old animals. In this paper, we present a mechanism by which GH eliminates age-dependent negative control of proliferation and increases transcription of liver-specific genes in livers of old mice. The reduced proliferative capacities of the liver of old animals are associated with the CCAAT/enhancer-binding protein alpha (C/EBPalpha)-Brm complex, which inhibits E2F-dependent promoters. We found that a sequestration of C/EBPalpha into complexes with Brm leads to a weak interaction of C/EBPalpha with promoters of liver-specific genes, expression of which is reduced in old animals. Injection of either GH or the regulator of the amplitude of endogenous GH release, ghrelin, reduces the C/EBPalpha-Brm complex in livers of old mice, leading to a derepression of E2F targets, to increased interactions of C/EBPalpha with promoters of liver-specific genes, and to correction of their expression. GH-dependent elimination of the complex is mediated by the inhibition of cyclin D3-CDK4 activity and by elevation of a phosphatase, protein phosphatase 2A, which dephosphorylates C/EBPalpha and dissociates the complex.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Aging / physiology*
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Animals
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Base Sequence
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CCAAT-Enhancer-Binding Protein-alpha / metabolism*
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Cell Division / drug effects
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Cell Division / physiology
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Cyclin D3
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Cyclin-Dependent Kinase 4 / metabolism
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Cyclin-Dependent Kinase 6 / metabolism
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Cyclins / metabolism
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Down-Regulation / physiology
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Forkhead Box Protein M1
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Forkhead Transcription Factors / genetics
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / physiology
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Ghrelin
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Growth Hormone / metabolism
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Growth Hormone / pharmacology*
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Liver / enzymology
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Mice
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Molecular Sequence Data
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Peptide Hormones / pharmacology
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Phosphoenolpyruvate Carboxykinase (GTP) / genetics*
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Phosphoenolpyruvate Carboxykinase (GTP) / metabolism
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Phosphoprotein Phosphatases / metabolism
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Phosphorylation
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Promoter Regions, Genetic / physiology
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Protein Phosphatase 2
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Transcription Factors / metabolism*
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Transcription, Genetic / drug effects
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Transcription, Genetic / physiology
Substances
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CCAAT-Enhancer-Binding Protein-alpha
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Ccnd3 protein, mouse
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Cyclin D3
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Cyclins
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Forkhead Box Protein M1
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Forkhead Transcription Factors
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Foxm1 protein, mouse
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Ghrelin
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Peptide Hormones
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Smarca2 protein, mouse
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Transcription Factors
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Growth Hormone
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Phosphoprotein Phosphatases
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Protein Phosphatase 2
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Phosphoenolpyruvate Carboxykinase (GTP)