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

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 (PPARbeta). PPARbeta 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 PPARbeta. Interestingly, activation of PPARbeta enhanced the mRNA expression of CerK and CerK activity. Furthermore, the cell survival effect of PPARbeta was greatly diminished in keratinocytes isolated from CerK-null mice. Chromatin immunoprecipitation revealed that, in vivo, PPARbeta binds to the CerK gene via a sequence located in the first intron. Electrophoretic mobility-shift assays confirmed that PPARbeta associates with this sequence in vitro. These findings indicated that CerK gene expression was directly regulated by PPARbeta. In conclusion, our results demonstrate that PPARbeta-mediated upregulation of CerK gene expression is necessary for keratinocyte survival against serum starvation-induced apoptosis.