The mammalian nuclear receptor superfamily of evolutionarily related DNA-binding transcription factors consists of approximately 50 members, many of which mediate gene expression in a ligand-dependent manner. From their functional similarities, nuclear receptors are divided into A-F regions that include the N-terminal A/B region, the highly conserved DNA-binding domain (DBD; C region), the C-terminal ligand-binding domain (LBD; E/F region), and the D region, which serves as a hinge between the C and the E/F regions. The A/B and the E/F regions contain ligand-independent activation function (AF-1) and ligand-dependent activation function (AF-2), respectively. 1-3) Nuclear receptors regulate gene expression through interactions with coregulator complexes along with the general transcriptional machinery. 4,5) The coregulators associating with the C-terminal region that mediate AF-2 are well documented, whereas the proteins interacting with the N-terminal region that mediate AF-1 and the mechanism involved are not well defined.
6)Liver receptor homolog-1 (LRH-1; NR5A2), part of the nuclear receptor family, is a monomeric orphan receptor initially identified as mammalian homolog of Drosophila Fushi tarazu factor 1 (NR5A3).7-10) The closest mammalian homolog of LRH-1 is steroidogenic factor-1 (SF-1; NR5A1), which is essential for the development and differentiation of steroidgenic tissues and sexual differentiation.11,12) LRH-1 is highly expressed in the liver and intestine involved in enterohepatic circulation, and the ovary. 7,9,13,14) LRH-1 is also expressed in the pancreas, placenta, and pre-adipocyte. 7,15,16) To date, four isoforms of LRH-1, referred to as LRH-1 v1 (NM_205860), 10) LRH-1 (NM_003822), 9,10) fetoprotein transcription factor (FTF; U93553), 17) and LRH-1 v2 (35-323 aa, AF049102), 17) have been reported. The most abundant isoform in liver is LRH-1 (NM_003822) which lacks 46 amino acid residues corresponding to exon 2. 9) LRH-1 v2 is a truncated version of LRH-1 with a deletion in the D region that corresponds to exon5, and does not possess transactivation activity.7) FTF, the N-terminally truncated isoform, is identical to LRH-1 except for a deletion in the A/B region of LRH-1 v1.LRH-1 plays an important role in the homeostasis of bile acids and cholesterol, controlling the expression of a number of genes, including small heterodimer partner (SHP; NR0B2) 18,19) and enzymes for the conversion of cholesterol to bile acids (CYP7A1 and CYP8B1) 10,20) and for high density lipoprotein-remodeling.21) In addition, LRH-1 contributes to development and ovulation.14,22,23) Unlike most nuclear receptors, LRH-1 binds to the LRH-1 response element (LRHRE) (5Ј-YCAAGGYCR-3Ј, Y; pyrimidine, R; purine), three base-pairs longer than the consensus nuclear receptor half-site, as a monomer.
7)Nuclear receptors typically regulate transcription in a ligand-dependent fashion. The binding of a ligand causes the repositioning of helix 12 within the LBD resulting in interaction with the coactivators.1-3) However, the mechanisms...
