Augmentation of Butyrate-induced Differentiation of Human Hepatocyte by Cyclin E Over-expression

Abstract

In mammalian cells, cellular differentiation into specific cell types is usually preceded by growth arrest. On the other hand, the induced differentiation may also be preceded by an enhanced G1–S transition of the cell cycle prior to the growth arrest. This suggests that an early increase in proliferation is in some way a prerequisite for subsequent differentiation. We therefore attempted to assess whether we could produce human hepatocytes with further differentiated functions by promoting G1-S transition in a butyrate-treated human hepatocyte cell line. A cyclin E-over-expressing cell line was established by transfecting human cyclin E cDNA. Upon butyrate treatment, the cyclin E-over-expressing cells exhibited a significantly increased albumin-secreting and ammonia-detoxifying capacity when compared to the control cells. In particular, the ornithine transcarbamylase activity was increased in these cells. Collectively, these results implicate that the cyclin E over-expression may augment the hepatocyte-specific functions during the butyrate-induced differentiation process of human hepatocytes by enhancing G1-S cell cycle transition.

Retinoblastoma Protein Modulates the Inverse Relationship between Cellular Proliferation and Elastogenesis

“…The pro-proliferative signals that activate cyclin-D-cdk4/6 complexes to induce Rb phosphorylation on its serine residues 780 and 795 (Ser-780/795) cause the release of E2F and allow for transcription of E2F-responsive genes, required for the cell cycle initiation (29 -34, 40, 43). Although the activations of the cyclin A and cyclin E complexes with cdk2 have been linked to the propagation through S-phase the cell cycle (44,45), these active complexes have also been identified in the non-proliferating cells, suggesting their role(s) in other cellular processes (46 -49). Meaningfully, the binding of Rb to the transcription factors belonging to the Sp-family of zinc-finger proteins has been linked to the activation of numerous genes contributing to cellular differentiation (50 -54) as well as to the activation of elastin transcription (27,28).…”