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SHORT COMMUNICATION

CERAMIDE, AN APOPTOTIC RHEOSTAT, INHIBITS CCAAT/ENHANCER BINDING PROTEIN-ß AND NF-E2-RELATED FACTOR-2 ACTIVATION: THE ROLE IN GLUTATHIONE S-TRANSFERASE A2 GENE REPRESSION

National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea

Ceramide is a sphingolipid that acts as a second messenger in signaling systems. Sphingomyelinase generates ceramide in response to cytotoxic stimuli. CCAAT/enhancer binding protein-ß (C/EBPß) and NF-E2-related factor-2 (Nrf2) are both involved in the regulation of the genes encoding phase II detoxification enzymes including glutathione S-transferase (GST). In the present study, we examined the effects of ceramide on C/EBPß or Nrf2 activation and on the inducible GSTA2 gene transactivation. C2-ceramide (C2), a cell-permeable analog, inhibited GSTA2 induction by oltipraz or tert-butylhydroquinone (t-BHQ) in H4IIE cells, whereas dihydro-C2-ceramide (dihydro-C2), an inactive analog, had no effect. Immunoblot analysis revealed that C2 prevented increase in the level of nuclear C/EBPß by oltipraz, whereas the level of C/EBPß in total cell lysates was not changed. Increase in nuclear Nrf2 by t-BHQ was also prevented by C2 treatment. Decreases in nuclear C/EBPß and Nrf2 by C2 were reversed by treatment of cells with N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132), a proteasome inhibitor, verifying the previous observations that the transcription factors were degraded by the proteasome system. In another study, we found that ceramide decreased nuclear hepatic nuclear factor-1 (HNF1), whose binding to the HNF1-response element in the GSTA2 gene was responsible for the constitutive and inducible gene expression. To define the role of C/EBPß or Nrf2 repression in GST expression under the condition excluding the negative regulation by C2-mediated HNF1 suppression, luciferase activity was determined in the cells transfected with HNF-pGL-1651 plasmid lacking the HNF1-response element. In the cells transfected with HNF-pGL-1651, C2 decreased the luciferase induction by oltipraz or t-BHQ. Thus, ceramide inhibits C/EBPß or Nrf2 activation, which contributes to repression of GSTA2 gene transactivation.

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