Carcinogenesis, Vol. 20, No. 7, 1209-1213,
July 1999
© 1999 Oxford University Press
Cancer Biology |
G1-arrested FaO cells re-enter the cell cycle upon stimulation with the rodent non-genotoxic hepatocarcinogen nafenopin
Zeneca Central Toxicology Laboratory, Cancer Biology Group,Alderley Park, Macclesfield SK10 4TJ, UK
The peroxisome proliferators are rodent non-genotoxic hepatocarcinogens that suppress apoptosis and induce DNA replication, cell proliferation and liver tumours. In order to investigate the effect of peroxisome proliferators on cell cycle progression, we arrested the well-differentiated rat hepatoma cell line FaO in the G1 phase of the cell cycle. Under these conditions, CDK2 and CDK4 protein expression remained unchanged compared with proliferating cells, but expression of cyclin D1 and p27KIP1 was down-regulated and cyclin E accumulated in the inactive form. G1-arrested cells were able to enter the cell cycle on addition of exogenous growth factors such as epidermal growth factor (EGF) or hepatocyte growth factor (HGF) and replicate their DNA within 12 to 24 h of re-stimulation. Upon release from G1 arrest, CDK2 protein expression was down-regulated and, surprisingly, p27KIP1 expression was restored. Cyclin D1 and phosphorylated cyclin E accumulated at 12 h but were degraded by 24 h after addition of EGF. Importantly, the peroxisome proliferator nafenopin and tumour necrosis factor 
were able to induce DNA replication. Thus, the profile of expression of cell cycle regulatory proteins upon stimulation with nafenopin is comparable with that induced by growth factors such as EGF.
Abbreviations: CDK, cyclin-dependent kinase; CKIs, cyclin-dependent kinase inhibitors; EGF, epidermal growth factor; FCS, fetal calf serum; HGF, hepatocyte growth factor; PBS, phosphate-buffered saline; PMSF, phenylmethylsulfonyl fluoride; PPAR, peroxisome proliferator activated receptor ; TNF, tumour necrosis factor .
1 To whom correspondence should be addressed Email: stephan.chevalier{at}ctl.zeneca.com
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. A. Canuto, G. Muzio, M. Maggiora, A. Trombetta, G. Martinasso, R. Autelli, P. Costelli, G. Bonelli, and F. M. Baccino Apoptosis induced by clofibrate in Yoshida AH-130 hepatoma cells: role of HMG-CoA reductase J. Lipid Res., January 1, 2003; 44(1): 56 - 64. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.-C. Kim, H.-T. Kim, M. Mamura, I. S. Ambudkar, K.-S. Choi, and S.-J. Kim Tumor Necrosis Factor Induces Apoptosis in Hepatoma Cells by Increasing Ca2+ Release from the Endoplasmic Reticulum and Suppressing Bcl-2 Expression J. Biol. Chem., August 23, 2002; 277(35): 31381 - 31389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. J. Elcock, E. Deag, R. A. Roberts, and J. K. Chipman Nafenopin Causes Protein Kinase C-Mediated Serine Phosphorylation and Loss of Function of Connexin 32 Protein in Rat Hepatocytes without Aberrant Expression or Localization Toxicol. Sci., July 1, 2000; 56(1): 86 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Chevalier, N Macdonald, and R. Roberts Induction of DNA replication by peroxisome proliferators is independent of both tumour necrosis factor (alpha) priming and EGF-receptor tyrosine kinase activity J. Cell Sci., January 12, 1999; 112(24): 4785 - 4791. [Abstract] [PDF]
|
|