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Glutathione S-Transferases (GSTs) Inhibit Transcriptional Activation by the Peroxisomal Proliferator-Activated Receptor γ (PPARγ) Ligand, 15-Deoxy-ΔProstaglandin J (15-d-PGJ )

Biochemistry, ISSN: 0006-2960, Vol: 43, Issue: 8, Page: 2345-2352
2004
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15-Deoxy-ΔProstaglandin J (15-d-PGJ ), a terminal metabolite of the J-series cyclopentenone prostaglandins, influences a variety of cellular processes including gene expression, differentiation, growth, and apoptosis. As a ligand of peroxisomal proliferator-activated receptor γ (PPARγ), 15-d-PGJ can transactivate PPARγ-responsive promoters. Previously, we showed that multidrug resistance proteins MRP1 and MRP3 attenuate cytotoxic and transactivating activities of 15-d-PGJ in MCF7 breast cancer cells. Attenuation was glutathione-dependent and was associated with formation of the glutathione conjugate of 15-d-PGJ, 15-d-PGJ-SG, and its active efflux by MRP. Here we have investigated whether the glutathione S-transferases (GST) can influence biological activities of 15-d-PGJ . MCF7 cells were stably transduced with human cytosolic GST isozymes M1a, A1, or P1a. These GSTs had no effect on 15-d-PGJ cytotoxicity when expressed either alone or in combination with MRP1. However, expression of any of the three GSTs significantly inhibited 15-d-PGJ -dependent transactivation of a PPARy-responsive reporter gene. The degree of inhibition correlated with the level of GST expressed. Under physiologic conditions, the nonenzymatic rate of 15-d-PGJ conjugation with glutathione was significant. Of the three GST isozymes, only GSTM1a-1a further stimulated the rate of 15-d-PGJ-SG formation. Moreover, GSTM1a-1a rate enhancement was only a transient burst that was complete within 15 s. Hence, catalysis plays little, if any, role in GST inhibifion of 15-d-PGJ-dependent transactivation. In contrast, inhibition of transactivation was associated with strong GST/15-d-PGJ interactions. Potent inhibition by 15-d-PGJ and 15-d-PGJ-SG of GST activity was observed with K in the 0.15-2.0 μM range for the three GST isozymes, results suggesting avid associations between GST and 15-d-PGJ or 15-d-PGJ-SG. Electrospray ionization mass spectrometry (ESI/MS) studies revealed no stable adducts of GST and 15-d-PGJ indicating that GST/15-d-PGJ interactions are primarily noncovalent. These results are consistent with a mechanism of GST-mediated inhibition of transactivation in which GST binds 15-d-PGJ and 15-d-PGJ-SG thereby sequestering the ligands in the cytosol away from their nuclear target, PPARγ.

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