An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway

S A Kliewer; J T Moore; L Wade; J L Staudinger; M A Watson; S A Jones; D D McKee; B B Oliver; T M Willson; R H Zetterström; T Perlmann; J M Lehmann

doi:10.1016/s0092-8674(00)80900-9

An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway

Cell. 1998 Jan 9;92(1):73-82. doi: 10.1016/s0092-8674(00)80900-9.

Authors

S A Kliewer¹, J T Moore, L Wade, J L Staudinger, M A Watson, S A Jones, D D McKee, B B Oliver, T M Willson, R H Zetterström, T Perlmann, J M Lehmann

Affiliation

¹ Department of Molecular Endocrinology, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.

PMID: 9489701
DOI: 10.1016/s0092-8674(00)80900-9

Abstract

Steroid hormones exert profound effects on differentiation, development, and homeostasis in higher eukaryotes through interactions with nuclear receptors. We describe a novel orphan nuclear receptor, termed the pregnane X receptor (PXR), that is activated by naturally occurring steroids such as pregnenolone and progesterone, and synthetic glucocorticoids and antiglucocorticoids. PXR exists as two isoforms, PXR.1 and PXR.2, that are differentially activated by steroids. Notably, PXR.1 is efficaciously activated by pregnenolone 16alpha-carbonitrile, a glucocorticoid receptor antagonist that induces the expression of the CYP3A family of steroid hydroxylases and modulates sterol and bile acid biosynthesis in vivo. Our results provide evidence for the existence of a novel steroid hormone signaling pathway with potential implications in the regulation of steroid hormone and sterol homeostasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Aryl Hydrocarbon Hydroxylases*
Base Sequence
Cloning, Molecular
Conserved Sequence / genetics
Conserved Sequence / physiology
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System / genetics
Embryo, Mammalian / chemistry
Embryo, Mammalian / metabolism
Gene Expression / genetics
Gene Expression / physiology
Genes / genetics
Glucocorticoids / chemical synthesis
Glucocorticoids / metabolism
Glucocorticoids / pharmacology
Histone Acetyltransferases
Mice
Molecular Sequence Data
Nuclear Receptor Coactivator 1
Oxidoreductases, N-Demethylating / genetics
Pregnane X Receptor
Pregnanes / chemical synthesis
Pregnanes / metabolism
Pregnanes / pharmacology*
Promoter Regions, Genetic / genetics
Promoter Regions, Genetic / physiology
Protein Binding
Receptors, Cytoplasmic and Nuclear / drug effects*
Receptors, Cytoplasmic and Nuclear / genetics*
Receptors, Cytoplasmic and Nuclear / physiology
Receptors, Steroid / genetics*
Signal Transduction
Steroids / physiology*
Transcription Factors / metabolism

Substances

Glucocorticoids
Pregnane X Receptor
Pregnanes
Receptors, Cytoplasmic and Nuclear
Receptors, Steroid
Steroids
Transcription Factors
Cytochrome P-450 Enzyme System
Aryl Hydrocarbon Hydroxylases
Cytochrome P-450 CYP3A
Oxidoreductases, N-Demethylating
Histone Acetyltransferases
Ncoa1 protein, mouse
Nuclear Receptor Coactivator 1

Associated data

GENBANK/AF031814