Growth Hormone Corrects Proliferation and Transcription of Phosphoenolpyruvate Carboxykinase in Livers of Old Mice via Elimination of CCAAT/Enhancer-binding Protein α-Brm Complex

Guo-Li Wang,Xiurong Shi,Elizabeth Salisbury,Yuxiang Sun,Jeffrey H Albrecht,Roy G Smith,Nikolai A Timchenko

doi:10.1074/jbc.m608226200

Guo-Li Wang, Xiurong Shi + Show 5 more

Open Access

https://doi.org/10.1074/jbc.m608226200

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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.

Highlights

Sequestration of C/EBP␣ into Complexes with Brm Reduces Association of C/EBP␣ with PEPCK and HNF6 Promoters in Livers of Old Mice—A number of recent publications revealed that C/EBP␣ displays its functions via formation of multiple protein-protein complexes
Since our previous studies showed that phosphorylation of C/EBP␣ at Ser193 is critical for the interaction with Brm [4, 10], we examined the phosphorylated status of C/EBP␣ in livers from old mice treated with growth hormone (GH)
GH Reduces CDK4/CDK6 Activity in Old Livers by Downregulation of Cyclin D3—We have shown that the presence of a phosphate on Ser193 depends on the balance of activities of CDK4/CDK6 and PP2A and that aging increases phosphorylation of Ser193 by activation of CDK4/CDK6 through elevation of cyclin D3 [4]

Summary

Introduction

In livers of old mice, the major portion of C/EBP␣ is associated with Brm and located on E2F-dependent promoters, where the complex represses transcription of cell cycle genes, such as c-Myc and FoxM1B. Western blotting with specific antibodies showed that protein levels of cyclin D3 are reduced in livers from old mice treated with GH (Fig. 4A).

Results

Conclusion