Tumor suppressor protein p53 negatively regulates human pregnane X receptor activity. Mol Pharmacol 83:1229–1236

The human pregnane X receptor (PXR) regulates genes in-volved in drug metabolism and disposition. PXR associates with multiple corepressors that attenuate and coactivators that enhance its activity. PXR plays a vital role in the drugmetabolism pathway, and a comprehensive examination of PXR-associated proteins will provide greater insight into the regulation of the receptor and possible therapeutic implications. We performed a mass spectrometric screen to identify PXR-associated proteins. Here we report that the tumor suppressor protein p53 can associate with PXR and downregulate its activity. A loss-of-function p53 mutant (R175H) interacts with PXR but does not repress its activity. Mutant p53 can relieve the suppressive effect of wild-type p53 by competing with its interaction with PXR, suggesting that protein-protein interaction is required but not sufficient for p53 to repress PXR activity. Interestingly, a PXR variant with a naturally occurring deletion of a conserved, unique sequence in the ligand binding domain (PXRΔ174–210) did not interact with p53, indicating that the PXR-p53 interaction is specific. Using a chromatin immunoprecipitation assay, we showed that p53 inhibits the binding of PXR to the CYP3A4 promoter. The loss of p53 function in tumor cells leads to aber-rant cell proliferation, apoptosis, carcinogenesis, and altered sensitivity to chemotherapeutic drugs, whereas PXR contributes to chemoresistance in many cancer cells. Our findings show for the first time that wild-type p53 can negatively regulate PXR by physically associating with it. Thus, PXR and p53 appear to play important yet opposing roles in the sensitivity of tumor cells to chemotherapy