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J. Biol. Chem., Vol. 278, Issue 28, 25853-25858, July 11, 2003

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Amino Acids Regulate Hepatocyte Proliferation through Modulation of Cyclin D1 Expression^*

Christopher J. Nelsen  , David G. Rickheim , Melissa M. Tucker , Travis J. McKenzie , Linda K. Hansen ¶, Richard G. Pestell || and Jeffrey H. Albrecht   **

From the Division of Gastroenterology, Hennepin County Medical Center, Minneapolis, Minnesota 55415, the Minneapolis Medical Research Foundation, Minneapolis, Minnesota 55404, the ^¶Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, and the ^||Department of Oncology, Georgetown University, Washington, D. C. 20057

The mechanisms by which amino acids regulate the cell cycle are not well characterized. In this study, we examined the control of hepatocyte proliferation by amino acids and protein intake. In short-term culture, hepatocytes demonstrated normal entry into S phase and cell cycle protein expression in the absence of essential amino acids. However, deprivation of a set of nonessential amino acids (NEAA) potently inhibited cell cycle progression and selectively down-regulated the expression of proliferation-control proteins. Notably, NEAA withdrawal after the mitogen restriction point still inhibited entry into S phase, suggesting that these amino acids regulate a distinct checkpoint. Cyclin D1, an important mediator of hepatocyte proliferation, was markedly inhibited at the transcriptional level by NEAA deprivation, and transfection with cyclin D1 (but not cyclin E) overcame the cell cycle arrest. As previously shown, protein-deprived mice demonstrated impaired hepatocyte proliferation in vivo after 70% partial hepatectomy. The expression of cyclin D1 and downstream cell cycle proteins after partial hepatectomy was inhibited in these mice. Transfection with cyclin D1 in vivo triggered hepatocyte DNA synthesis and the expression of S phase proteins in the absence of dietary protein. Cyclin D1 also induced global protein synthesis in NEAA-deprived hepatocytes and promoted liver growth in vivo in the setting of protein deprivation. These results indicate that cyclin D1 is a key target of amino acid signaling in hepatocytes.

Received for publication, March 6, 2003 , and in revised form, April 25, 2003.

^* This work was supported by National Institutes of Health Grants DK54921 and P50 AT00009 – 04. 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.

^** To whom correspondence should be addressed: Division of Gastroenterology (865B), Hennepin County Medical Center, 701 Park Ave., Minneapolis, MN 55415. Tel.: 612-347-8582; Fax: 612-904-4366; E-mail: albre010{at}tc.umn.edu.

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