Journal Article

Role of MAP kinase signalling pathways in the mode of action of peroxisome proliferators

Sabina Cosulich, Neil James and Ruth Roberts

in Carcinogenesis

Volume 21, issue 4, pages 579-584
Published in print April 2000 | ISSN: 0143-3334
Published online April 2000 | e-ISSN: 1460-2180 | DOI:
Role of MAP kinase signalling pathways in the mode of action of peroxisome proliferators

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Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis. In primary rat hepatocytes, PPs cause cell proliferation, suppression of apoptosis and peroxisome proliferation. We have investigated the role of different families of mitogen-activated protein (MAP) kinases in the mode of action of PPs. Addition of 50 μM nafenopin to primary rat hepatocyte cultures caused weak activation of extracellular signal regulated kinases and p38 MAP kinase. However, incubation of primary hepatocytes with the p38 MAP kinase inhibitor SB203580 or the MAP kinase kinase (MEK) inhibitor PD098059 prevented the induction of DNA synthesis and the suppression of transforming growth factor β1-induced apoptosis by the PP nafenopin. In contrast, in the presence of these MAP kinase inhibitors, nafenopin still induced palmitoyl CoA oxidation, a measure of peroxisome proliferation. We have shown previously that PPs such as nafenopin require tumour necrosis factor α (TNF-α) to exert their effects on cellular proliferation and apoptosis. Here we show that treatment of primary rat hepatocyte cultures with nafenopin causes an increase in bioactive TNF-α and that this process requires p38 MAP kinase activity.

Keywords: AMC, 7-amino-4-methyl-coumarin; BrdU, bromodeoxyuridine; CIPCO, cyanide-insensitive palmitoyl CoA oxidation; EGF, epidermal growth factor; MAP kinase, mitogen-activated kinase; PP, peroxisome proliferator; PPAR, peroxisome proliferator activated receptor; TGF-β1, transforming growth factor β1; TNF-α, tumour necrosis factor α.

Journal Article.  3935 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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