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J. Biol. Chem., Vol. 282, Issue 2, 1468-1478, January 12, 2007

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

Guo-Li Wang, Xiurong Shi, Elizabeth Salisbury, Yuxiang Sun, Jeffrey H. Albrecht^¶, Roy G. Smith^||, and Nikolai A. Timchenko¹

From the Huffington Center on Aging and Departments of Pathology and ^||Molecular Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 and the ^¶Division of Gastroenterology, Hennepin County Medical Center, Minneapolis, Minnesota 55415

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 (C/EBP)-Brm complex, which inhibits E2F-dependent promoters. We found that a sequestration of C/EBP into complexes with Brm leads to a weak interaction of C/EBP 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/EBP-Brm complex in livers of old mice, leading to a derepression of E2F targets, to increased interactions of C/EBP 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/EBP and dissociates the complex.

Received for publication, August 28, 2006 , and in revised form, October 25, 2006.

^* This work was supported by National Institutes of Health Grants CA10070, GM55188, and AG025477 (to N. A. T.), DK54921 (to J. H. A.), AG18895, and AG19230 (to R. G. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pathology and Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-1567; Fax: 713-798-4161; E-mail: nikolait{at}bcm.tmc.edu.

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