title: Long-term extracellular signal-related kinase activation following cadmium intoxication is negatively regulated by a protein kinase C-dependent pathway affecting cadmium transport.
abstract: Extracellular signal-related kinase (ERK) is a well-known kinase taking part in a signal transduction cascade in response to extracellular stimuli. ERK is generally viewed as a kinase that is rapidly and transiently phosphorylated following mitogenic stimulation. This activation results in ERK phosphorylating further downstream targets, thus transmitting and amplifying the original stimulus, and ultimately resulting in the onset of cellular proliferation and/or protection against apoptosis. More recently, several groups have identified a strikingly new type of ERK activation that results in cell death. This activation is very different from conventional ERK activation, as it occurs several hours after the original stimulation, and results in the sustained phosphorylation of ERK, which can be observed for up to several days. One way of inducing this delayed ERK activation is by low-dose cadmium treatment. We show here that sustained ERK activation induced by cadmium in human kidney-derived cells is inhibited following protein kinase C (PKC) activation, even when this activation occurs hours before intoxication. Furthermore, PKC inhibition results in an enhanced ERK activation in response to cadmium, even when inhibition is induced hours before intoxication. PKCepsilon appears to be the most implicated isotype in this phenomenon. Finally, we present evidence suggesting that the ZIP8 transporter is involved in this process, as multiple small interfering RNAs against ZIP8 have a protective effect against cadmium treatment. Our results indicate that PKC activation negatively affects ZIP8 transporter activity, thus protecting cells against cadmium poisoning.
authors.affiliation: CNRS FRE3094, Université de Nice Sophia Antipolis, Nice, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Martin
authors.forename: Kim E
authors.initials: KE
authors.lastname: Boulukos
authors.forename: Marie C
authors.initials: MC
authors.lastname: Poggi
authors.forename: Philippe
authors.initials: P
authors.lastname: Pognonec
mesh_terms: D002104:Cadmium / Q000493:pharmacokinetics / Q000633:toxicity*; D027682:Cation Transport Proteins / Q000235:genetics / Q000502:physiology; D015536:Down-Regulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D027682:Cation Transport Proteins; D004791:Enzyme Inhibitors; C530151:SLC39A8 protein, human; D002104:Cadmium; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate