FOR, a Novel Orphan Nuclear Receptor Related to Farnesoid X Receptor

Abstract

We have identified and characterized a new amphibian orphan member of the nuclear receptor superfamily and termed it FOR1 (farnesoid X receptor (FXR)-like Orphan Receptor) because it shares the highest amino acid identity with the mammalian FXR. We also identi- The nuclear receptor superfamily comprises a large group of structurally related ligand-dependent transcription factors regulated by a variety of steroid and non-steroid hormones. It also includes a large number of related proteins that do not have known ligands, referred to as orphan nuclear receptors (reviewed in Refs. 1-3). The nuclear receptors modulate target gene transcription by direct binding to specific DNA sequences, called hormone response elements (HRE), 1 which are generally located in the promoter of the specific target genes. In general, both classic nuclear hormone receptors and orphan nuclear hormone receptors consist of four or five different modules or domains; A/B, C, D, E, and F (1). The non-conserved N-terminal region of nuclear receptors (A/B domain) is involved in transactivation in some cases but is of unknown function or is absent in others. The DNA-binding C-domain (DBD) shows the strongest sequence similarity among different nuclear receptors and is engaged in the binding of these receptors to cognate HREs. The C-domain consists of 65-68 amino acids, among which 8 cysteine residues are absolutely conserved and form two zincbinding modules (1, 3, 4). The D-domain, called the hinge region, shows relatively low sequence similarity and contains sequences involved in HRE binding at its N terminus. The E-domain directly binds to ligands or hormones and is also involved in nuclear localization and receptor dimerization. The C terminus of the LBD contains a conserved motif that, together with other portions of the LBD, forms the binding site for transcriptional coactivators (1). The F-domain is an additional C-terminal extension found in only subset of receptors. The function of this non-conserved segment is unclear.A large number of orphan nuclear receptor genes have been discovered by several different approaches. These include 1) screening cDNA libraries with conventional receptor cDNA probes at relaxed stringency (5) or with degenerate oligonucleotides based on the conserved regions (6), 2) performing PCR with degenerate oligonucleotide PCR primers from the DBD (7, 8), 3) screening cDNA libraries using nuclear receptor ligand binding domains (LBD) or receptor interaction domains of coactivators as bait in a yeast two-hybrid system (9, 10).

Induction of cardiomyocytes by GATA4 inXenopusectodermal explants

“…3B) and severe reduction in the formation of anterior endodermal tissue, such as liver, as judged by LFABP (Fig. 3F) and For1 (Seo et al, 2002) (data not shown). The apparent synergism between SOX17βEnR and GATA4 in promoting cardiac tissue differentiation suggests that GATA4 may induce endoderm at B. V. Latinkić, S. Kotecha and T. J. Mohun the expense of cardiac tissue.…”

“…15-20 animal caps were used per sample. The templates for riboprobes were: MHCα (Logan and Mohun, 1993), MLC2 (Chambers et al, 1994), cTnI , IFABP (Shi and Hayes, 1994), Sox17α (Hudson et al, 1997), MyoD (Hopwood et al, 1989), MLC1 (Theze et al, 1995), Eomesodermin , globin (Patient et al, 1982), Nkx2.3 (Evans et al, 1995), Nkx2.5 , For1 (Seo et al, 2002), EF1α, amylase and insulin (Horb and Slack, 2002). For the LFABP probe, we used the 5′ end of cDNA [derived by 5′ RACE using partial cDNA information; see Henry and Melton (Henry and Melton, 1998)].…”

Ligand specificity and evolution of liver X receptors

“…The high degree of conservation of the vertebrate LXRs contrasts with divergence of FXRs across species. For example, the Xenopus laevis FXR has markedly different pharmacology from mammalian FXRs and also has a novel insert in the LBD not found in human or rodent FXRs [37].…”

Identification of intermediates in the bile acid synthetic pathway as ligands for the farnesoid X receptor

“…Human FXR may have retained affinity for these precursors during evolution. A recent study has shown that FXR-like orphan receptors (FORs), identified in Xenopus laevis liver and kidney, are not activated by bile acids but are activated by bullfrog gallbladder bile extracts (52), which contain bile alcohols (53).…”