MAPK-ERK activation in kidney of male rats chronically fed ochratoxin A at a dose causing a significant incidence of renal carcinoma

Journal Article · Mon Oct 15 04:00:00 EDT 2007 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2007.06.014· OSTI ID:21077825

Nestler, S ^[1]; Verguet, C; Bezencon, C; Piguet, D; Delatour, T ^[2]; Mantle, P ^[3]; Cavin, C; Schilter, B ^[2]

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1. Nephro-Urology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1E 1EH (United Kingdom)
2. Nestle Research Center, PO Box 44, Vers-chez-les-Blanc, CH-1000 Lausanne 26 (Switzerland)
3. Department of Environmental Science and Technology, Imperial College London, London SW7 2AZ (United Kingdom)

Kidney samples of male Fischer 344 (F-344) rats fed a carcinogenic dose of OTA over 7 days, 21 days and 12 months were analysed for various cell signalling proteins known to be potentially involved in chemical carcinogenicity. OTA was found to increase the phosphorylation of atypical-PKC. This was correlated with a selective downstream activation of the MAP-kinase extracellular regulated kinases isoforms 1 and 2 (ERK1/2) and of their substrates ELK1/2 and p90RSK. Moreover, analysis of effectors acting upstream of PKC indicated a possible mobilisation of the insulin-like growth factor-1 receptor (lGFr) and phosphoinositide-dependent kinase-1 (PDK1) system. An increased histone deacetylase (HDAC) enzymatic activity associated with enhanced HDAC3 protein expression was also observed. These findings are potentially relevant with respect to the understanding of OTA nephrocarcinogenicity. HDAC-induced gene silencing has previously been shown to play a role in tumour development. Furthermore, PKC and the MEK-ERK MAP-kinase pathways are known to play important roles in cell proliferation, cell survival, anti-apoptotic activity and renal cancer development.

• OSTI ID: 21077825
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 224; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CARCINOMAS
CELL PROLIFERATION
DOSES
GROWTH FACTORS
INSULIN
KIDNEYS
PHOSPHORYLATION
PHOSPHOTRANSFERASES
RATS
RECEPTORS