The pregnane X receptor regulates gene expression in a ligand- and promoter-selective fashion

Hisashi Masuyama, Naoko Suwaki, Yoko Tateishi, Hideki Nakatsukasa, Tomonori Segawa, Yuji Hiramatsu

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Recent studies have revealed that pregnane X receptor (PXR) can function as a master regulator to control the expression of phase I and phase II drug-metabolizing enzymes, as well as members of the drug transporter family, including multiple drug resistance (MDR) 1, which has a major role in multidrug resistance. Previously, we have demonstrated that steroid/xenobiotics metabolism by tumor tissue through the PXR-cytochrome P-450 3A (CYP3A) pathway might play an important role in endometrial cancer. In this study, we examined which endocrine-disrupting chemicals (EDCs) and anticancer agents might be ligands for PXR and whether these chemicals enhanced PXR-mediated transcription through two different PXR-responsive elements (PXREs), CYP3A4 and MDR1, in endometrial cancer cell lines. Some steroids/EDCs strongly activated PXR-mediated transcription through the CYP3A4-responsive element compared with the MDR1-responsive element, whereas these steroids/EDCs also enhanced the CYP3A4 expression compared with the MDR1 expression. In contrast, the anticancer agents, cisplatin and paclitaxel, strongly activated PXR-mediated transcription through the MDR1-responsive element compared with the CYP3A4-responsive element, whereas these drugs also enhanced the MDR1 expression compared with the CYP3A4 expression. We also analyzed how these ligands regulated PXR-mediated transcription through two different PXREs. In the presence of PXR ligands, there was no difference in the DNA binding affinity of the PXR/retinoid X receptor heterodimer to each PXRE, but there were different interactions of the coactivator to each PXR/PXRE complex. These data suggested that PXR ligands enhanced PXR-mediated transcription in a ligand- and promoter-dependent fashion, which in turn differentially regulated the expression of individual PXR targets, especially CYP3A4 and MDR1.

Original languageEnglish
Pages (from-to)1170-1180
Number of pages11
JournalMolecular Endocrinology
Volume19
Issue number5
DOIs
Publication statusPublished - May 2005

Fingerprint

Ligands
Gene Expression
Cytochrome P-450 CYP3A
Endocrine Disruptors
Steroids
Multiple Drug Resistance
Endometrial Neoplasms
pregnane X receptor
Antineoplastic Agents
Pharmaceutical Preparations
Retinoid X Receptors
Xenobiotics
Cytochrome P-450 Enzyme System
Cell Line
DNA
Enzymes

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

The pregnane X receptor regulates gene expression in a ligand- and promoter-selective fashion. / Masuyama, Hisashi; Suwaki, Naoko; Tateishi, Yoko; Nakatsukasa, Hideki; Segawa, Tomonori; Hiramatsu, Yuji.

In: Molecular Endocrinology, Vol. 19, No. 5, 05.2005, p. 1170-1180.

Research output: Contribution to journalArticle

Masuyama, H, Suwaki, N, Tateishi, Y, Nakatsukasa, H, Segawa, T & Hiramatsu, Y 2005, 'The pregnane X receptor regulates gene expression in a ligand- and promoter-selective fashion', Molecular Endocrinology, vol. 19, no. 5, pp. 1170-1180. https://doi.org/10.1210/me.2004-0434
Masuyama, Hisashi ; Suwaki, Naoko ; Tateishi, Yoko ; Nakatsukasa, Hideki ; Segawa, Tomonori ; Hiramatsu, Yuji. / The pregnane X receptor regulates gene expression in a ligand- and promoter-selective fashion. In: Molecular Endocrinology. 2005 ; Vol. 19, No. 5. pp. 1170-1180.
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