EGFR: A Master Piece in G1/S Phase Transition of Liver Regeneration.

Alexandra Collin De L'Hortet,Hélène Gilgenkrantz,Jacques-Emmanuel Guidotti

doi:10.1155/2012/476910

Abstract

Unraveling the molecular clues of liver proliferation has become conceivable thanks to the model of two-third hepatectomy. The synchronicity and the well-scheduled aspect of this process allow scientists to slowly decipher this mystery. During this phenomenon, quiescent hepatocytes of the remnant lobes are able to reenter into the cell cycle initiating the G1-S progression synchronously before completing the cell cycle. The major role played by this step of the cell cycle has been emphasized by loss-of-function studies showing a delay or a lack of coordination in the hepatocytes G1-S progression. Two growth factor receptors, c-Met and EGFR, tightly drive this transition. Due to the level of complexity surrounding EGFR signaling, involving numerous ligands, highly controlled regulations and multiple downstream pathways, we chose to focus on the EGFR pathway for this paper. We will first describe the EGFR pathway in its integrity and then address its essential role in the G1/S phase transition for hepatocyte proliferation. Recently, other levels of control have been discovered to monitor this pathway, which will lead us to discuss regulations of the EGFR pathway and highlight the potential effect of misregulations in pathologies.

Highlights

Mammals have almost completely lost the fascinating regeneration capacities of amphibians, their liver retained this unique ability
We can hypothesize that β-catenin pathway compensates for epidermal growth factor receptor (EGFR) defect in GH receptor knockout mice (GHrKO) mice from mid G1-phase when EGFR expression was reinduced. These data highlight the major role played by growth factors via EGFR in the liver regeneration process
Its activation during the G1 phase controls the cell cycle progression of hepatocytes from the G1 phase until the S phase leading to the synchronized hepatocytes S-phase entry

Summary

Introduction

Mammals have almost completely lost the fascinating regeneration capacities of amphibians, their liver retained this unique ability. Hepatocyte proliferation is preceded by an inflammatory stimulus, described in the pioneering work of Nelson Fausto as the “priming phase” [1, 2] This first step is reversible since, without the subsequent involvement of growth factors, hepatocytes do not progress through cell cycle and return to quiescence. Mitchell et al showed that after 1/3 PH in mice, there is a lack of a synchronous wave of DNA replication [21] They observed that, among the growth factors induced during liver regeneration, the secretion peak of HB-EGF usually observed 24 h after 2/3 PH was absent after the 1/3 PH [21]. Besides highlighting the robust mitogen potential of HB-EGF, this study indicated the importance of the EGFR pathway in the synchronous induction of DNA replication in a dose-dependent manner after PH

EGFR Pathway

EGFR Pathway during the G1-S Phase in Hepatocytes

Regulation of the EGFR Pathway during Liver Regeneration

Findings

Conclusion