Induction of apoptosis and inhibition of papilloma formation may signal a new role for okadaic acid

There is substantial interest in identifying agents that differentially activate keratinocyte differentiation versus apoptosis. Okadaic acid (OA) is a tumor promoter in mouse skin that also stimulates apoptosis of murine keratinocytes. OA also enhances human keratinocyte differentiation; however, the impact of OA treatment on apoptosis in these cells has not been examined. We show that OA promotes normal human keratinocyte apoptosis as evidenced by increased accumulation of cells having sub-G1/S DNA content, decreased mitochondrial integrity, increased annexin V binding, increased cytoplasmic cytochrome c level, and increased procaspase 3 and PARP cleavage. Cyclin A, cyclin D1, cdk2, cdk4, p53 and p21 levels are reduced. These changes are associated with release of the PKCdelta catalytic domain and increased phosphorylation of PKCdelta-T(505)-responses consistent with PKCdelta activation. In contrast, phosphorylation of PKCdelta-Y(311) is not increased. The apoptotic response is enhanced in OA treated cells in the presence of p38delta, a PKCdelta target. OA treatment selectively activated p38delta, and OA-dependent apoptosis is not inhibited by treatment with the p38alpha/beta inhibitor, SB203580. These findings are consistent with the idea that the response is mediated by p38delta. Our data indicate that OA is an agent that regulates both keratinocyte differentiation and apoptosis, and that this regulation is mediated via activation of a PKCdelta/p38delta signaling cascade.

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Activation of PKCδ and p38δ MAPK during okadaic acid dependent keratinocyte apoptosis

Kraft

Efimova

Eckert

2007

Arch Dermatol Res

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Quantitative proteomic analysis of okadaic acid treated mouse small intestines reveals differentially expressed proteins involved in diarrhetic shellfish poisoning

Wang

Lin

et al. 2012

Journal of Proteomics

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Degradation and Dephosphorylation of Focal Adhesion Kinase During Okadaic Acid-Induced Apoptosis in Human Neuroblastoma Cells

2003

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Focal adhesion kinase (FAK) prevents apoptosis in many cell types. We have reported that tyrosine residues in FAK are dephosphorylated and FAK is degraded during mannitol-induced apoptosis in human neuroblastoma cells. Several studies suggest that FAK dephosphorylation and degradation are separate events. The current study defines the relationship between FAK dephosphorylation and degradation in neuroblastoma cells using okadaic acid (OA). OA, a serine phosphatase inhibitor, promotes serine/threonine phosphorylation, which in turn blocks tyrosine phosphorylation. OA induced focal adhesion loss, actin cytoskeleton disorganization, and cellular detachment, which corresponded to a loss of FAK Tyr397 phosphorylation. These changes preceded caspase-3 activation, Akt and MAP kinase activity loss, protein ubiquitination, and cellular apoptosis. Insulin-like growth factor-I prevented mannitol-induced, but not OA-induced, substrate detachment and FAK Tyr397 dephosphorylation, and the effects of OA on FAK Tyr397 phosphorylation were irreversible. The proteolytic degradation of FAK is temporally distinct from its tyrosine dephosphorylation, occurring when apoptotic pathways are already initiated and during a generalized destruction of signaling proteins. Therefore, agents resulting in the dephosphorylation of FAK may be beneficial for therapeutic treatment, irrespective of FAK protein levels, as this may result in apoptosis, which cannot be prevented by growth factor signaling.

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Induction of apoptosis and inhibition of papilloma formation may signal a new role for okadaic acid

Cited by 6 publications

References 34 publications

Activation of PKCδ and p38δ MAPK during okadaic acid dependent keratinocyte apoptosis

Activation of PKCδ and p38δ MAPK during okadaic acid dependent keratinocyte apoptosis

Quantitative proteomic analysis of okadaic acid treated mouse small intestines reveals differentially expressed proteins involved in diarrhetic shellfish poisoning

Degradation and Dephosphorylation of Focal Adhesion Kinase During Okadaic Acid-Induced Apoptosis in Human Neuroblastoma Cells

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