Mitogen activated protein kinases selectively regulate palytoxin- stimulated gene expression in mouse keratinocytes

Nicholette A. Zeliadt, Janel K. Warmka, Elizabeth V Wattenberg

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)212-221
Number of pages10
JournalToxicology and Applied Pharmacology
Issue number3
StatePublished - Nov 1 2003

Bibliographical note

Funding Information:
We thank Dr. Stuart Yuspa for contributing the 308 cell lines. This work was supported by Research Project Grant #RPG-00-290-01-TBE from the American Cancer Society.

Copyright 2017 Elsevier B.V., All rights reserved.


  • JNK
  • Keratinocytes
  • Matrix metalloproteinase-13
  • Mitogen activated protein kinases
  • Signal transduction
  • Tumor promoters
  • p38

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