Induction of hepatocyte proliferation and liver hyperplasia by the targeted expression of cyclin E and skp2

Cells in culture become competent to replicate in the absence of growth fac tor after progressing beyond the late G1 restriction point, suggesting that a set of genes expressed during G1 phase is sufficient to trigger completi on of the cell cycle. However, this has not been demonstrated in an in vivo system. In this study, we examined whether transfection of genes associate d with the G1/S transition could trigger hepatocyte replication. Co-transfe ction of cyclin E and skp2 synergistically promoted cell cycle progression in cultured primary hepatocytes in the absence of mitogen or in the presenc e of growth inhibitors. Furthermore, transfection of hepatocytes in vivo wi th cyclin E and skp2 promoted abundant hepatocyte replication and hyperplas ia of the liver. These studies confirm that transfection with a small numbe r of genes can trigger proliferation of quiescent hepatocytes in vivo, and suggest that therapies to enhance liver regeneration by targeting cell cycl e control genes may be feasible.