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J. Biol. Chem., Vol. 280, Issue 4, 2562-2568, January 28, 2005

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Heparin-binding Epidermal Growth Factor-like Growth Factor Links Hepatocyte Priming with Cell Cycle Progression during Liver Regeneration^*

Claudia Mitchell, Mary Nivison, Leslie F. Jackson, Richard Fox, David C. Lee, Jean S. Campbell, and Nelson Fausto¶

From the Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195 and Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599

The mechanisms that regulate the transition between the initial priming phase and DNA replication in liver regeneration are poorly understood. To study this transition, we compared events occurring after standard two-thirds partial hepatectomy, which elicits full regeneration, with response to a reduced hepatectomy, one-third partial hepatectomy (1/3PH), which leads to little DNA replication. Although the initial response to partial hepatectomy at the priming phase appeared to be similar between the two procedures, cell cycle progression was significantly blunted in 1/3PH mice. Among the main defects observed in 1/3PH mice were an almost complete deficiency in retinoblastoma phosphorylation and the lack of increase in kinase activity associated with cyclin E. We report that, in two-thirds partial hepatectomy mice, the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) preceded the start of DNA replication and was not detectable in 1/3PH animals. Injection of HB-EGF into 1/3PH mice resulted in a >15-fold increase in DNA replication. Moreover, we show that hepatocyte DNA replication was delayed in HB-EGF knock-out mice. In summary, we show that HB-EGF is a key factor for hepatocyte progression through G₁/S transition during liver regeneration.

Received for publication, November 2, 2004

^* This work was supported by Grants CA-23226 and CA-43793 from the National Institutes of Health and by Fondation pour la Recherche Médicale (FRM-France) and the Philippe Foundation (to C. 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.

^¶ To whom correspondence should be addressed: Dept. of Pathology, University of Washington, K-078 HSB, Box 357705, Seattle, WA 98195. Tel.: 206-616-4550; Fax: 206-543-3967; E-mail: nfausto{at}u.washington.edu.

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