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Ligands Have Various Potential Effects on the Degradation of Pregnane X Receptor by Proteasome

Department of Obstetrics and Gynecology, Okayama University Medical School, Okayama 700-8558, Japan

Address all correspondence and requests for reprints to: Hisashi Masuyama, M.D., Ph.D., Department of Obstetrics and Gynecology, Okayama University Medical School, 2-5-1 Shikata, Okayama 700-8558, Japan. E-mail: masuyama{at}cc.okayama-u.ac.jp

The degradations of several nuclear receptors are involved in the proteasome-mediated pathway. In our recent experiments, we found that mouse pregnane X receptor (PXR) interacted with suppressor for gal1 (SUG1), a component of the proteasome, in a progesterone-dependent manner, but that endocrine-disrupting chemicals (EDCs), phthalic acid and nonylphenol, which activated PXR-mediated transcription, did not enhance this interaction. PXR protein levels were markedly increased in the presence of proteasome inhibitors, suggesting that PXR may be degraded by proteasome. Furthermore, in the absence of ongoing protein synthesis, there is much slower degradation of PXR in the presence of phthalic acid compared with that in the presence of progesterone. The transient expression studies demonstrated that overexpression of wild-type SUG1 generated proteolytic PXR fragments, and these productions were blocked by a proteasome inhibitor. Functionally, expression of SUG1 inhibited PXR- and progesterone-mediated transcription. Moreover, in the presence of EDCs, SUG1 had no effect on the transcription. These findings indicate that the interaction between PXR and SUG1 may be involved in the proteasome-mediated degradation. Moreover, an EDC strongly blocks the degradation of PXR compared with progesterone, suggesting that EDCs may affect PXR-mediated transcription of target genes through up-regulation of the PXR protein level.

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