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J. Biol. Chem., Vol. 282, Issue 29, 21244-21252, July 20, 2007

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Akt-mediated Liver Growth Promotes Induction of Cyclin E through a Novel Translational Mechanism and a p21-mediated Cell Cycle Arrest^*

Lisa K. Mullany, Christopher J. Nelsen, Eric A. Hanse, Melissa M. Goggin, Chelsea K. Anttila, Mark Peterson^¶, Peter B. Bitterman^¶, Arvind Raghavan, Gretchen S. Crary^||, and Jeffrey H. Albrecht^¶1

From the Division of Gastroenterology, Hennepin County Medical Center, Minneapolis, Minnesota 55415, the Minneapolis Medical Research Foundation, Minneapolis, Minnesota 55404, the ^¶Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, and the ^||Department of Pathology, Hennepin County Medical Center, Minneapolis, Minnesota 55415

The control of hepatocyte growth is relevant to the processes of liver regeneration, development, metabolic homeostasis, and cancer. A key component of growth control is the protein kinase Akt, which acts downstream of mitogens and nutrients to affect protein translation and cell cycle progression. In this study, we found that transient transfection of activated Akt triggered a 3-4-fold increase in liver size within days but only minimal hepatocyte proliferation. Akt-induced liver growth was associated with marked up-regulation of cyclin E but not cyclin D1. Analysis of liver polyribosomes demonstrated that the post-transcriptional induction of cyclin E was associated with increased translational efficiency of this mRNA, suggesting that cell growth promotes expression of this protein through a translational mechanism that is distinct from the cyclin D-E2F pathway. Treatment of Akt-transfected mice with rapamycin only partially inhibited liver growth and did not prevent the induction of cyclin E protein, indicating that target of rapamycin activity is not necessary for this response. In the enlarged livers, cyclin E-Cdk2 complexes were present in high abundance but were inactive due to increased binding of p21 to these complexes. Akt transfection of p21^-/- mice promoted liver growth, activation of Cdk2, and enhanced hepatocyte proliferation. In conclusion, growth promotes cyclin E expression through a novel translational mechanism in the liver, suggesting a new link between cell growth and the cell cycle machinery. Furthermore, p21 suppresses proliferation in the overgrown livers and may play a role in preventing cell cycle progression in response to organ size homeostatic mechanisms.

Received for publication, March 12, 2007 , and in revised form, May 10, 2007.

^* This work was supported by National Institutes of Health Grant DK54921 (to J. H. A.) and a grant from the Minneapolis Medical Research Foundation (to L. K. M.). 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: Division of Gastroenterology, Hennepin County Medical Center (G5), 701 Park Ave., Minneapolis, MN 55415. Tel.: 612-873-8582; Fax: 612-904-4366; E-mail: albre010{at}umn.edu.

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