Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3-Phosphoinositide-Dependent Protein Kinases
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Animals
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Blotting, Western
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Carcinogens / administration & dosage
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Carcinogens / toxicity*
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Gene Expression Regulation / drug effects
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Histone Deacetylases / metabolism
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Kidney / metabolism
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Kidney Neoplasms / chemically induced
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Kidney Neoplasms / physiopathology
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MAP Kinase Signaling System / drug effects
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Male
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Mitogen-Activated Protein Kinase 1 / drug effects*
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / drug effects*
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Mitogen-Activated Protein Kinase 3 / metabolism
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Ochratoxins / administration & dosage
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Ochratoxins / toxicity*
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Phosphorylation
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Protein Serine-Threonine Kinases / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Rats
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Rats, Inbred F344
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Receptor, IGF Type 1 / drug effects
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Receptor, IGF Type 1 / metabolism
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Ribosomal Protein S6 Kinases, 90-kDa / drug effects
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism
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Time Factors
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ets-Domain Protein Elk-1 / drug effects
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ets-Domain Protein Elk-1 / metabolism
Substances
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Carcinogens
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Elk1 protein, rat
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Ochratoxins
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ets-Domain Protein Elk-1
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ochratoxin A
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Receptor, IGF Type 1
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3-Phosphoinositide-Dependent Protein Kinases
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Pdpk1 protein, rat
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Protein Serine-Threonine Kinases
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Ribosomal Protein S6 Kinases, 90-kDa
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Histone Deacetylases
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histone deacetylase 3