Journal Article

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

Sabina C. Cosulich, Neil H. James, Maurice R.C. Needham, Peter P. Newham, Ken R. Bundell and Ruth A. Roberts

in Carcinogenesis

Volume 21, issue 9, pages 1757-1760
Published in print September 2000 | ISSN: 0143-3334
Published online September 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.9.1757
A dominant negative form of IKK2 prevents suppression of apoptosis by the peroxisome proliferator nafenopin

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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-β1. Tumour necrosis factor α (TNF-α) and the transcription factor NFκB have been implicated in the mode of action of PPs. TNF-α signalling to NFκB is thought to be responsible for many of the effects elicited by this cytokine. NFκB regulates gene expression in immunity, stress responses and the inhibition of apoptosis. Activation of NFκB requires the successive action of NFκB-inducing kinase and the phosphorylation of NFκB inhibitory proteins (IκB) by an IκB kinase (IKK) complex. The IKK2 subunit of IκB kinase is thought to be essential for NFκB 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-α. Moreover, IKK2dn-induced apoptosis could not be rescued by addition of TNF-α 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.

Keywords: GFP, green fluorescent protein; PPs, peroxisome proliferators; rIAP-1, rat inhibitor of apoptosis-1; TGF-β1, transforming growth factor-β1; TNF-α, tumour necrosis factor α; TNFR1, tumor necrosis factor α receptor 1.

Journal Article.  2250 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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