Green Tea Induced Cellular Proliferation and the Expression of Transforming Growth Factor-β1 in the Jejunal Mucosa of Fasting Rats

Abstract.Epidermal growth factor (EGF) causes proliferation in renal tubular cells but, when it is combined with transforming growth factor-β1, it causes hypertrophy by a mechanism that requires the activity of the retinoblastoma family of proteins. In contrast, ammonia causes hypertrophy by decreasing lysosomal proteolysis; in some cell types, it also decreases cellular proliferation. These studies were designed to determine whether ammonia, like transforming growth factor-β1, could convert EGF-induced hyperplasia to hypertrophy. Cultured NRK-52E cells were incubated with EGF and/or ammonia and the protein/DNA ratio was measured, as a marker of hypertrophy. Addition of ammonia to EGF-treated NRK-52E cells converted EGF-induced hyperplasia to hypertrophy, because of a decrease in DNA synthesis. The mechanism involved no change in EGF-induced protein synthesis. Inhibition of lysosomal function with a proton pump inhibitor or lysosomal protease inhibitors also converted the response of EGF-treated cells to hypertrophy. Expression of the human papilloma virus 16 E7 protein (which inactivates all members of the retinoblastoma family) prevented ammonia from converting EGF-induced hyperplasia to hypertrophy. It is concluded that ammonia converts EGF-induced hyperplasia to hypertrophy by a mechanism that involves suppression of lysosomal function and this response can be blocked by inhibiting the activity of the retinoblastoma family of proteins.

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Iron chelation-induced senescence-like growth arrest in hepatocyte cell lines: association of transforming growth factor β1 (TGF-β1)-mediated p27Kip1 expression

Biochemical Journal ◽

10.1042/bj20011445 ◽

2002 ◽

Vol 366 (2) ◽

pp. 613-621 ◽

Cited By ~ 51

Author(s):

Gyesoon YOON ◽

Hyun-Jung KIM ◽

Young-Sil YOON ◽

Hyeseong CHO ◽

In K. LIM ◽

...

Keyword(s):

Cell Cycle ◽

Growth Factor ◽

Cell Lines ◽

Cellular Proliferation ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

G1 Arrest ◽

Cyclin Dependent Kinase ◽

Negative Cell ◽

Tgf Β1

Iron is essential for cellular proliferation in all organisms. When deprived of iron, the growth of cells is invariably inhibited. However, the mechanism involved remains largely unclear. In the present study, we have observed that subcytotoxic concentrations of desferroxamine mesylate (DFO), an iron chelator, specifically inhibited the transition from G1 to S-phase of Chang cells, a hepatocyte cell line. This was accompanied by the appearance of senescent biomarkers, such as enlarged and flattened cell morphology, senescence-associated β-galactosidase activity and reduced expression of poly(ADP-ribose) polymerase. Concomitantly, p27Kip1 (where Kip is kinase-inhibitory protein) was induced markedly, whereas other negative cell-cycle regulators, such as p21Cip1 (where Cip is cyclin-dependent kinase-interacting protein), p15INK4B and p16INK4A (where INK is inhibitors of cyclin-dependent kinase 4), were not, implying its association in the G1 arrest. Furthermore, the induction of p27Kip1 was accompanied by an increased level of transforming growth factor β1 (TGF-β1) mRNA. When neutralized with an anti-(TGF-β1) antibody, p27Kip1 induction was completely abolished, indicating that TGF-β1 is the major inducer of p27Kip1. Finally, DFO-induced senescence-like arrest was found to be independent of p53, since cell-cycle arrest was still observed with two p53-negative cell lines, Huh7 and Hep3B cells. In conclusion, DFO induced senescence-like G1 arrest in hepatocyte cell lines and this was associated with the induction of p27Kip1 through TGF-β1, but was independent of p53.

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