Mitogen activated protein kinases selectively regulate palytoxin-stimulated gene expression in mouse keratinocytes.
We have been investigating how the novel skin tumor promoter palytoxin transmits signals through mitogen activated protein kinases (MAPKs). Palytoxin activates three major MAPKs, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, in a keratinocyte cell line derived from initiated mouse skin (308). We previously showed that palytoxin requires ERK to increase matrix metalloproteinase-13 (MMP-13) gene expression, an enzyme implicated in carcinogenesis. Diverse stimuli require JNK and p38 to increase MMP-13 gene expression, however. We therefore used the JNK and p38 inhibitors SP 600125 and SB 202190, respectively, to investigate the role of these MAPKs in palytoxin-induced MMP-13 gene expression. Surprisingly, palytoxin does not require JNK and p38 to increase MMP-13 gene expression. Accordingly, ERK activation, independent of palytoxin and in the absence of JNK and p38 activation, is sufficient to induce MMP-13 gene expression in 308 keratinocytes. Dexamethasone, a synthetic glucocorticoid that inhibits activator protein-1 (AP-1), blocked palytoxin-stimulated MMP-13 gene expression. Therefore, the AP-1 site present in the promoter of the MMP-13 gene appears to be functional and to play a key role in palytoxin-stimulated gene expression. Previous studies showed that palytoxin simulates an ERK-dependent selective increase in the c-Fos content of AP-1 complexes that bind to the promoter of the MMP-13 gene. JNK and p38 can also modulate c-Fos. Palytoxin does not require JNK or p38 to increase c-Fos binding, however. Altogether, these studies indicate that ERK plays a distinctly essential role in transmitting palytoxin-stimulated signals to specific nuclear targets in keratinocytes derived from initiated mouse skin.
Division of Environmental and Occupational Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA.
Nicholette A
NA
Zeliadt
Janel K
JK
Warmka
Elizabeth V
EV
Wattenberg
D000178:Acrylamides / Q000633:toxicity; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002461:Cell Line, Transformed; D003064:Cnidarian Venoms / Q000633:toxicity; D017364:Collagenases / Q000096:biosynthesis / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D007093:Imidazoles / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology*; D053509:Matrix Metalloproteinase 13; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D000095702:Polyether Toxins
D000178:Acrylamides; D000873:Anthracenes; D003064:Cnidarian Venoms; D017364:Collagenases; D003907:Dexamethasone; D004791:Enzyme Inhibitors; D007093:Imidazoles; D053509:Matrix Metalloproteinase 13; D020928:Mitogen-Activated Protein Kinases; D011725:Pyridines; C432165:pyrazolanthrone; C507081:Mmp13 protein, mouse; C010272:palytoxin; D000095702:Polyether Toxins; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole