Role of ceramide kinase in peroxisome proliferator-activated receptor beta-induced cell survival of mouse keratinocytes

Authors

  • Kiyomi Tsuji,

    1.  Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Advanced Life Sciences, Hokkaido University, Sapporo, Japan
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  • Susumu Mitsutake,

    1.  Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
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  • Urara Yokose,

    1.  Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
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  • Masako Sugiura,

    1.  Biological Research Laboratories II, Daiichi-Sankyo Co. Ltd., Tokyo, Japan
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  • Takafumi Kohama,

    1.  Exploratory Research Laboratories I, Daiichi-Sankyo Co. Ltd., Tokyo, Japan
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  • Yasuyuki Igarashi

    1.  Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Advanced Life Sciences, Hokkaido University, Sapporo, Japan
    2.  Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
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Y. Igarashi, Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Pharmaceutical Sciences and Faculty of Advanced Life Sciences, Hokkaido University, Nishi 6, Kita 12, Kita-ku, Sapporo 060-0812, Japan
Fax: +81 11 706 4986
Tel: +81 11 706 3970
E-mail: yigarash@pharm.hokudai.ac.jp Website: http://biomem.pharm.hokudai.ac.jp/english/index.html

Abstract

Ceramide (Cer) is known to be a lipid mediator in apoptosis and to have an important role in cell fate, via control of intracellular Cer levels. Recently, ceramide kinase (CerK) was identified as an enzyme that converts Cer to ceramide 1-phosphate (C1P). We examined potential functions of CerK in the regulation of keratinocyte survival, and the possible involvement of peroxisome proliferator-activated receptor beta (PPARβ). PPARβ is known to be a nuclear receptor acting as a ligand-inducible transcription factor and has been implicated in the control of keratinocyte survival. In the mouse keratinocyte cell line SP1, serum starvation induced cell death and the accumulation of intracellular Cer, an apoptotic event. However, apoptosis was inhibited by activation of PPARβ. Interestingly, activation of PPARβ enhanced the mRNA expression of CerK and CerK activity. Furthermore, the cell survival effect of PPARβ was greatly diminished in keratinocytes isolated from CerK-null mice. Chromatin immunoprecipitation revealed that, in vivo, PPARβ binds to the CerK gene via a sequence located in the first intron. Electrophoretic mobility-shift assays confirmed that PPARβ associates with this sequence in vitro. These findings indicated that CerK gene expression was directly regulated by PPARβ. In conclusion, our results demonstrate that PPARβ-mediated upregulation of CerK gene expression is necessary for keratinocyte survival against serum starvation-induced apoptosis.

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