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

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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-Y311 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.

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Acknowledgments

This work utilized the facilities of the Skin Diseases Research Center of Northeast Ohio (NIH, AR39750) and was supported by grants to R. Eckert from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, OH, 44106-4970, USA

    Catherine A. Kraft & Richard L. Eckert

  2. Department of Biochemistry, Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, OH, 44106-4970, USA

    Richard L. Eckert

  3. Department of Reproductive Biology, Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, OH, 44106-4970, USA

    Richard L. Eckert

  4. Department of Oncology, Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, OH, 44106-4970, USA

    Richard L. Eckert

  5. Department of Dermatology, Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, OH, 44106-4970, USA

    Richard L. Eckert

  6. Division of Dermatology, Washington University School of Medicine, St. Louis, MO, USA

    Tatiana Efimova

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  1. Catherine A. Kraft
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Kraft, C.A., Efimova, T. & Eckert, R.L. Activation of PKCδ and p38δ MAPK during okadaic acid dependent keratinocyte apoptosis. Arch Dermatol Res 299, 71–83 (2007). https://doi.org/10.1007/s00403-006-0727-4

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