MAPK-ERK activation in kidney of male rats chronically fed ochratoxin A at a dose causing a significant incidence of renal carcinoma.
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.
Marin-Kuan
M
M
Nestlé Research Center, PO Box 44, Vers-chez-les-Blanc, CH-1000 Lausanne 26, Switzerland. maricel.marin-kuan@rdls.nestle.com
Nestler
S
S
Verguet
C
C
Bezençon
C
C
Piguet
D
D
Delatour
T
T
Mantle
P
P
Cavin
C
C
Schilter
B
B
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects* / Q000378:metabolism; D009793:Ochratoxins / Q000008:administration & dosage / Q000633:toxicity*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D050807:ets-Domain Protein Elk-1 / Q000187:drug effects / Q000378:metabolism; D000099186:Histone Deacetylase 3
D064413:3-Phosphoinositide-Dependent Protein Kinases; D002273:Carcinogens; D006655:Histone Deacetylases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009793:Ochratoxins; D017346:Protein Serine-Threonine Kinases; D017526:Receptor, IGF Type 1; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D050807:ets-Domain Protein Elk-1; D000099186:Histone Deacetylase 3; C494114:Elk1 protein, rat; C025589:ochratoxin A; C578579:Pdpk1 protein, rat