Extracellular Signal-Regulated Kinase Transmits Palytoxin-Stimulated Signals Leading to Altered Gene Expression in Mouse Keratinocytes

Warmka, Janel K.

doi:10.1006/taap.2002.9519

Cited by 15 publications

(25 citation statements)

References 52 publications

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“…We previously reported that palytoxin modulates c-Fos in 308 mouse keratinocytes (Warmka et al, 2002). We concluded that palytoxin modulated c-Fos through an ERK1/2-dependent pathway based on the observation that the ability of palytoxin to increase c-Fos levels was blocked by PD98059, which inhibits MEK1/2, the kinases that phosphorylate and activate ERK1/2.…”

Section: Resultsmentioning

confidence: 99%

“…We previously demonstrated that although palytoxin and TPA bind to different cellular receptors, the initially distinct signaling pathways stimulated by palytoxin and TPA can converge to regulate common downstream targets, including ERK1/2 (Warmka et al, 2002). In contrast to palytoxin, however, TPA did not stimulate a detectable increase in ERK5 phosphorylation in either cell line (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In general ERK1/2 tends to be activated by mitogenic agents, whereas JNK and p38 are typically activated by stress (Turjanski et al, 2007). Our work indicates that MAPKs can mediate the convergence of the different signaling pathways stimulated by palytoxin and TPA, thus providing a mechanism by which these different types of tumor promoters can regulate common biochemical targets that play an important role in carcinogenesis (Warmka et al, 2002; Warmka et al, 2004). For example, we found that palytoxin and TPA both increase ERK1/2 activity, although by different mechanisms, in mouse keratinocytes that are derived from initiated mouse skin and express oncogenic Ras (308 cells); this results in the ability of palytoxin and TPA to regulate common downstream nuclear targets, including the transcription factor AP-1 (Warmka et al, 2002; Warmka et al, 2004; Zeliadt et al, 2004).…”

Section: Introductionmentioning

confidence: 85%

“…Palytoxin binding thus typically triggers sodium influx and potassium efflux. Our previous studies indicated that mitogen activated protein kinases (MAPKs) can mediate palytoxin-stimulated signaling (Kuroki et al, 1997; Li and Wattenberg, 1999; Warmka et al, 2002; Warmka et al, 2004). …”

Section: Introductionmentioning

confidence: 99%

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Extracellular signal regulated kinase 5 mediates signals triggered by the novel tumor promoter palytoxin

Charlson

Zeliadt

Wattenberg

2009

Toxicology and Applied Pharmacology

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Palytoxin is classified as a non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type skin tumor because it does not bind to or activate protein kinase C. Palytoxin is thus a novel tool for investigating alternative signaling pathways that may affect carcinogenesis. We previously showed that palytoxin activates three major members of the mitogen activated protein kinase (MAPK) family, extracellular signal regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. Here we report that palytoxin also activates another MAPK family member, called ERK5, in HeLa cells and in keratinocytes derived from initiated mouse skin (308 cells). By contrast, TPA does not activate ERK5 in these cell lines. The major cell surface receptor for palytoxin is the Na+,K+-ATPase. Accordingly, ouabain blocked the ability of palytoxin to activate ERK5. Ouabain alone did not activate ERK5. ERK5 thus represents a divergence in the signaling pathways activated by these two agents that bind to the Na+,K+-ATPase. Cycloheximide, okadaic acid, and sodium orthovandate did not mimic the effect of palytoxin on ERK5. These results indicate that the stimulation of ERK5 by palytoxin is not simply due to inhibition of protein synthesis or inhibition of serine/threonine or tyrosine phosphatases. Therefore, the mechanism by which palytoxin activates ERK5 differs from that by which it activates ERK1/2, JNK, and p38. Finally, studies that used pharmacological inhibitors and shRNA to block ERK5 action indicate that ERK5 contributes to palytoxin-stimulated c-Fos gene expression. These results suggest that ERK5 can act as an alternative mediator for transmitting diverse tumor promoter-stimulated signals.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Extracellular signal regulated kinase 5 mediates signals triggered by the novel tumor promoter palytoxin

Charlson

Zeliadt

Wattenberg

2009

Toxicology and Applied Pharmacology

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“…Moreover, we showed that the potent skin tumor promoter palytoxin stimulates the downregulation of MKP-3 in keratinocytes derived from initiated mouse skin, which express oncogenic Ras ( Warmka et al, 2002 ). This further suggests that MKP-3 is an important negative regulator in carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Reciprocal regulation of extracellular signal regulated kinase 1/2 and mitogen activated protein kinase phosphatase-3

Zeliadt¹,

Mauro²,

Wattenberg³

2008

Toxicology and Applied Pharmacology

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Mitogen activated protein kinase phosphatase-3 (MKP-3) is a putative tumor suppressor. When transiently overexpressed, MKP-3 dephosphorylates and inactivates extracellular signal regulated kinase (ERK) 1/2. Little is known about the roles of endogenous MKP-3, however. We previously showed that MKP-3 is upregulated in cell lines that express oncogenic Ras. Here we tested the roles of endogenous MKP-3 in modulating ERK1/2 under conditions of chronic stimulation of the Ras/ Raf/MEK1/2/ERK1/2 pathway by expression of oncogenic Ras. We used two cell lines: H-ras MCF10A, breast epithelial cells engineered to express H-Ras, and DLD-1, colon cancer cells that express endogenous Ki-Ras. First, we found that MKP-3 acts in a negative feedback loop to suppress basal ERK1/2 when oncogenic Ras stimulates the Ras/Raf/MEK1/2/ERK1/2 cascade. ERK1/2 was required to maintain elevated MKP-3, indicative of a negative feedback loop. Accordingly, knockdown of MKP-3, via siRNA, increased ERK1/2 phosphorylation. Second, by using siRNA, we found that MKP-3 helps establish the sensitivity of ERK1/2 to extracellular activators by limiting the duration of ERK1/2 phosphorylation. Third, we found that the regulation of ERK1/2 by MKP-3 is countered by the complex regulation of MKP-3 by ERK1/2. Potent ERK1/2 activators stimulated the loss of MKP-3 within 30 minutes due to an ERK1/2-dependent decrease in MKP-3 protein stability. MKP-3 levels recovered within 120 minutes due to ERK1/2-dependent resynthesis. Preventing MKP-3 resynthesis, via siRNA, prolonged ERK1/2 phosphorylation. Altogether, these results suggest that under the pressure of oncogenic Ras expression, MKP-3 reins in ERK1/2 by serving in ERK1/2-dependent negative feedback pathways. KeywordsMitogen activated protein kinase phosphatase-3; extracellular signal regulated kinase; Ras *Corresponding author.

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Pharmacology of palytoxins and ostreocins

2015

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Extracellular Signal-Regulated Kinase Transmits Palytoxin-Stimulated Signals Leading to Altered Gene Expression in Mouse Keratinocytes

Cited by 15 publications

References 52 publications

Extracellular signal regulated kinase 5 mediates signals triggered by the novel tumor promoter palytoxin

Extracellular signal regulated kinase 5 mediates signals triggered by the novel tumor promoter palytoxin

Reciprocal regulation of extracellular signal regulated kinase 1/2 and mitogen activated protein kinase phosphatase-3

Pharmacology of palytoxins and ostreocins

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