Extracellular signal regulated kinase 5 mediates signals triggered by the novel tumor promoter palytoxin
- Division of Environmental Health Sciences, School of Public Health, University of Minnesota, Mayo Mail Code 807, 420 Delaware Street Southeast, Minneapolis, MN 55455 (United States)
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 orthovanadate 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.
- OSTI ID:
- 21344796
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 241, Issue 2; Other Information: DOI: 10.1016/j.taap.2009.08.021; PII: S0041-008X(09)00366-4; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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ACETATES
CARCINOGENESIS
CYCLOHEXIMIDE
ENZYME INHIBITORS
GENES
HELA CELLS
MICE
NEOPLASMS
OUABAIN
PHOSPHATASES
RECEPTORS
SERINE
SIGNALS
SKIN
SODIUM COMPOUNDS
STIMULATION
SYNTHESIS
THREONINE
TUMOR PROMOTERS
TYROSINE
VANADATES
ALKALI METAL COMPOUNDS
AMINO ACIDS
ANIMAL CELLS
ANIMALS
ANTIBIOTICS
ANTI-INFECTIVE AGENTS
BODY
CARBOHYDRATES
CARBOXYLIC ACID SALTS
CARBOXYLIC ACIDS
CARDIAC GLYCOSIDES
CARDIOTONICS
CARDIOVASCULAR AGENTS
DISEASES
DRUGS
ENZYMES
ESTERASES
FUNGICIDES
GLYCOSIDES
HYDROLASES
HYDROXY ACIDS
MAMMALS
MEMBRANE PROTEINS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
OXYGEN COMPOUNDS
PATHOGENESIS
PESTICIDES
PROMOTERS
PROTEINS
RODENTS
STROPHANTHINS
TRANSITION ELEMENT COMPOUNDS
TUMOR CELLS
VANADIUM COMPOUNDS
VERTEBRATES