Growth hormone corrects proliferation and transcription of phosphoenolpyruvate carboxykinase in livers of old mice via elimination of CCAAT/enhancer-binding protein alpha-Brm complex.
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.
Wang
Guo-Li
GL
Huffington Center on Aging and Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Shi
Xiurong
X
Salisbury
Elizabeth
E
Sun
Yuxiang
Y
Albrecht
Jeffrey H
JH
Smith
Roy G
RG
Timchenko
Nikolai A
NA
D000375:Aging / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D056743:Cyclin D3; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D054439:Ghrelin; D013006:Growth Hormone / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D051379:Mice; D008969:Molecular Sequence Data; D036361:Peptide Hormones / Q000494:pharmacology; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D054648:Protein Phosphatase 2; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D022763:CCAAT-Enhancer-Binding Protein-alpha; C534697:Ccnd3 protein, mouse; D056743:Cyclin D3; D016213:Cyclins; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D054439:Ghrelin; D036361:Peptide Hormones; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; D013006:Growth Hormone; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D010729:Phosphoenolpyruvate Carboxykinase (GTP)