An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway.
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.
Kliewer
S A
SA
Department of Molecular Endocrinology, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.
Moore
J T
JT
Wade
L
L
Staudinger
J L
JL
Watson
M A
MA
Jones
S A
SA
McKee
D D
DD
Oliver
B B
BB
Willson
T M
TM
Zetterström
R H
RH
Perlmann
T
T
Lehmann
J M
JM
D000595:Amino Acid Sequence; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D003001:Cloning, Molecular; D017124:Conserved Sequence / Q000235:genetics / Q000502:physiology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004622:Embryo, Mammalian / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D005796:Genes / Q000235:genetics; D005938:Glucocorticoids / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051548:Histone Acetyltransferases; D051379:Mice; D008969:Molecular Sequence Data; D056920:Nuclear Receptor Coactivator 1; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D000077297:Pregnane X Receptor; D011278:Pregnanes / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D011987:Receptors, Steroid / Q000235:genetics*; D015398:Signal Transduction; D013256:Steroids / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D005938:Glucocorticoids; D000077297:Pregnane X Receptor; D011278:Pregnanes; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013256:Steroids; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1