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,Nelson Fausto

doi:10.1074/jbc.m412372200

Abstract

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 G(1)/S transition during liver regeneration.

Highlights

The mechanisms that regulate the transition between the initial priming phase and DNA replication in liver regeneration are poorly understood
Liver Regeneration Is Delayed in heparin-binding epidermal growth factor-like growth factor (HB-EGF) Knock-out Mice— Because of the large differential sensitivity to HB-EGF and TGF-␣ effects demonstrated in 1/3PH mice (Fig. 5) and the earlier timing of the expression of HB-EGF during liver regeneration (Fig. 4C), we investigated whether HB-EGF knock-out mice would have defects in liver regeneration
It is well established that hepatocyte DNA replication in the regenerating mouse liver does not start until ϳ30 h after partial hepatectomy

Summary

Introduction

The mechanisms that regulate the transition between the initial priming phase and DNA replication in liver regeneration are poorly understood. The entry of quiescent hepatocytes into the cell cycle, corresponding to the G0/G1 transition, is largely regulated by cytokines This phase, often referred to as priming, is characterized by the increase in cytokines such as tumor necrosis factor-␣ and IL-6 and the activation of immediate early genes that include c-jun, c-fos, and c-myc [2]. We have previously demonstrated that continuous infusion of TGF-␣ or HGF for 24 h into the portal vein of rats with 30% hepatectomies or one-third partial hepatectomy (1/3PH) produced a vigorous replicative response to the growth factors [14] Together, these data indicated that 1/3PH, in contrast to the standard 2/3PH, may induce hepatocyte priming that does not progress to DNA replication. We reasoned that the analysis of events occurring after 1/3PH may uncover linkages between priming

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