Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (8)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Cosulich, S. C.
Right arrow Articles by Roberts, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cosulich, S. C.
Right arrow Articles by Roberts, R. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Carcinogenesis, Vol. 21, No. 9, 1757-1760, September 2000
© 2000 Oxford University Press

Short Communications

A dominant negative form of IKK2 prevents suppression of apoptosis by the peroxisome proliferator nafenopin

Sabina C. Cosulich2, Neil H. James1, Maurice R.C. Needham, Peter P. Newham, Ken R. Bundell and Ruth A. Roberts1

AstraZeneca Pharmaceuticals and
1 Zeneca Central Toxicology Laboratory, 3G8 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK

Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis. In primary rat hepatocyte cultures, PPs suppress spontaneous apoptosis and that induced by a number of pro-apoptotic stimuli such as transforming growth factor-ß1. Tumour necrosis factor {alpha} (TNF-{alpha}) and the transcription factor NF{kappa}B have been implicated in the mode of action of PPs. TNF-{alpha} signalling to NF{kappa}B is thought to be responsible for many of the effects elicited by this cytokine. NF{kappa}B regulates gene expression in immunity, stress responses and the inhibition of apoptosis. Activation of NF{kappa}B requires the successive action of NF{kappa}B-inducing kinase and the phosphorylation of NF{kappa}B inhibitory proteins (I{kappa}B) by an I{kappa}B kinase (IKK) complex. The IKK2 subunit of I{kappa}B kinase is thought to be essential for NF{kappa}B activation and prevention of apoptosis. To determine whether IKK2 plays a role in the suppression of apoptosis by PPs, we expressed a dominant negative form of IKK2 (IKK2dn) in primary rat hepatocyte cultures. Infection with an adenovirus construct expressing IKK2dn caused apoptosis in control primary rat hepatocytes in the absence of exogenous TNF-{alpha}. Moreover, IKK2dn-induced apoptosis could not be rescued by addition of TNF-{alpha} or the peroxisome proliferator nafenopin. These results demonstrate a requirement for intracellular signalling pathways mediated by IKK2 in the suppression of apoptosis by the PP class of hepatocarcinogens.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 CarcinogenesisHome page
D. J. Hoivik, C. W. Qualls Jr, R. C. Mirabile, N. F. Cariello, C. L. Kimbrough, H. M. Colton, S. P. Anderson, M. J. Santostefano, R. J. O. Morgan, R. R. Dahl, et al.
Fibrates induce hepatic peroxisome and mitochondrial proliferation without overt evidence of cellular proliferation and oxidative stress in cynomolgus monkeys
Carcinogenesis, September 1, 2004; 25(9): 1757 - 1769.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
S. Hasmall, G. Orphanides, N. James, W. Pennie, K. Hedley, A. Soames, I. Kimber, and R. Roberts
Downregulation of Lactoferrin by PPAR{alpha} Ligands: Role in Perturbation of Hepatocyte Proliferation and Apoptosis
Toxicol. Sci., August 1, 2002; 68(2): 304 - 313.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.