Orphan nuclear receptors: from new ligand discovery technologies to novel signaling pathways.
Members of the nuclear receptor superfamily of ligand-regulated transcription factors play critical roles in multiple aspects of development, cellular differentiation and homeostasis. The ligand-dependent transcriptional effects of nuclear receptors are, in part, mediated by interactions with a group of proteins collectively known as transcriptional coactivators. Receptor agonists promote coactivator binding and receptor antagonists suppress coactivator binding. Recently, biochemical assays that detect ligand-binding based on coactivator recruitment have been developed for several 'orphan' nuclear receptors, i.e., receptors for which no bona fide endogenous ligands are known. We review how these assays have been used to identify naturally occurring and synthetic ligands for the liver X receptor, farnesoid X receptor and estrogen receptor-related receptor subfamilies of orphans, the use of these ligands in the discovery of novel biological signaling pathways and the potential clinical implications of these findings.
Shiau
A K
AK
Tularik Inc., Two Corporate Drive, South San Francisco, CA 94080, USA.
Coward
P
P
Schwarz
M
M
Lehmann
J M
JM
D000595:Amino Acid Sequence; D000818:Animals; D004268:DNA-Binding Proteins; D015195:Drug Design; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D011960:Receptors, Estrogen / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D029867:Xenopus Proteins
D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D029867:Xenopus Proteins; C459605:farnesoid X receptor-like orphan receptor, Xenopus