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

Catherine A. Kraft, Tatiana Efimova, Richard L. Eckert*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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 PKCδ catalytic domain and increased phosphorylation of PKCδ-T505-responses consistent with PKCδ activation. In contrast, phosphorylation of PKCδ-Y 311 is not increased. The apoptotic response is enhanced in OA treated cells in the presence of p38δ, a PKCδ target. OA treatment selectively activated p38δ, and OA-dependent apoptosis is not inhibited by treatment with the p38α/β inhibitor, SB203580. These findings are consistent with the idea that the response is mediated by p38δ. 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 PKCδ/p38δ signaling cascade.

Original languageEnglish (US)
Pages (from-to)71-83
Number of pages13
JournalArchives of Dermatological Research
Volume299
Issue number2
DOIs
StatePublished - May 2007

Keywords

  • ERK1/2
  • Keratinocyte apoptosis
  • Okadaic acid
  • PKCδ
  • p38 MAPK

ASJC Scopus subject areas

  • Dermatology

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