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Iron chelation-induced senescence-like growth arrest in hepatocyte cell lines: association of transforming growth factor beta1 (TGF-beta1)-mediated p27Kip1 expression.

Authors
Yoon, G; Kim, HJ; Yoon, YS; Cho, H; Lim, IK; Lee, JH
Citation
The Biochemical journal, 366(Pt2):613-621, 2002
Journal Title
The Biochemical journal
ISSN
0264-60211470-8728
Abstract
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 beta-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 beta1 (TGF-beta1) mRNA. When neutralized with an anti-(TGF-beta1) antibody, p27Kip1 induction was completely abolished, indicating that TGF-beta1 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-beta1, but was independent of p53.
MeSH terms
AnimalsCell Aging/drug effects/*physiologyCell Cycle/drug effectsCell Cycle Proteins/*geneticsCell Division/drug effectsCell LineCyclin-Dependent Kinase Inhibitor p27Deferoxamine/*pharmacologyG1 Phase/drug effectsGenes, Tumor SuppressorHepatocytes/cytology/drug effects/*physiologyIron Chelating Agents/*pharmacologyPoly(ADP-ribose) Polymerases/metabolismRecombinant Proteins/metabolismReverse Transcriptase Polymerase Chain ReactionTransforming Growth Factor beta/*pharmacologyTumor Suppressor Proteins/*geneticsbeta-Galactosidase/metabolism
DOI
10.1042/BJ20011445
PMID
11945174
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
윤, 계순조, 혜성임, 인경이, 재호
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