A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements.

Abstract

We have identified and characterized a new orphan member of the nuclear hormone receptor superfamily, called MB67, which is predominantly expressed in liver. MB67 binds and transactivates the retinoic acid response elements that control expression of the retinoic acid receptor P2 and alcohol dehydrogenase 3 genes, both of which consist of a direct repeat hexamers related to the consensus AGGTCA, separated by 5 bp. MB67 binds these elements as a heterodimer with the 9-cis-retinoic acid receptor, RXR. However, MB67 does not bind or activate other retinoic acid response elements with alternative hexamer arrangements or any of several other wild-type and synthetic hormone response elements examined. The transactivation of retinoic acid response elements by MB67 is weaker than that conferred by the retinoic acid receptors but does not require the presence of all-trans retinoic acid, 9-cis-retinoic acid, or any exogenously added ligand. We propose that MB67 plays an important role in the complex network of proteins that govern response to retinoic acid and its metabolites.The nuclear hormone receptor superfamily is a large group of related transcription factors which includes members that bind a diverse array of ligands, including steroids, thyroid hormone (T3), all-trans retinoic acid (RA), 9-cis-retinoic acid (9-cis-RA), and vitamin D (reviewed in references 4,8,19,23,35). In mammals, approximately a dozen genes encode these conventional receptors. An even larger number of genes encode proteins known as orphan receptors (recently compiled in references 1 and 32). These orphans are structurally and functionally related to the conventional receptors but do not bind known ligands.The biological roles of the orphans are generally unknown. Some information is available for a limited number which were initially characterized prior to their identification as superfamily members. HNF-4, for example, was originally identified as a liver-specific basic transcription factor, with binding sites in several genes (59). Similarly, SF-I was identified as a factor associated with activation of expression of several steroidogenic enzymes (31). However, the majority of the orphans were isolated simply by cross-hybridization with probes derived from conventional receptors, and their functions remain largely undefined. By analogy with the conventional receptors, it has generally been thought that most of the orphans will eventually be demonstrated to be ligand-dependent transcriptional activators. However, recent results demonstrate that several, including 30,59), , and NGFI-B/Nur77 (13,48,70)

Redundant enhancement of mouse constitutive androstane receptor transactivation by p160 coactivator family members

“…This could be because PB activation of CAR is not associated with either the activation of a specific p160 coactivator or the translocation of any specific p160 to the nucleus so interaction of CAR with a specific p160 coactivator is not required. Alternatively, although CAR is expressed preferentially in liver, it is also expressed at lower levels in other tissues [25], and it is possible that redundancy of the p160 coactivators permits maximal activation of CAR in tissues that have different relative concentrations of the p160 coactivators.…”

Nuclear receptors CAR and PXR in the regulation of hepatic metabolism

“…Similar to PXR (also known as steroid and xenobiotic receptor SXR), CAR heterodimerizes with RXR and binds to the phenobarbital responsive enhancer module (PBREM) to induce the transcription of CYP2B genes (Baes et al 1994;Choi et al 1997;Honkakoski and Negishi 1997). Closer examination of the PBREM and the other CARregulated promoters revealed that CAR preferentially binds to DR4 (direct repeat spaced by 4 nucleotides) binding sites (Honkakoski et al 1998).…”

“…With few exceptions, NRs share a common domain based structure comprised of four fundamental domains: A/B domain containing the ligand independent activation function (AF-1), DNA binding domain (designated the C domain), hinge region of lesser defined function (D domain) and the E/F domain containing the ligand dependent activation function (AF-2) as well as the ligand binding domain. The most recent classification scheme for NRs is based on sequence homology in which both the constitutive active/androstane receptor (CAR) and pregnane X receptor (PXR) belong to the NR1I family (NR1I3 and NR1I2, respectively) (Baes et al 1994(Baes et al , 1999. The anti-seizure drugs phenobarbital (PB) and phenytoin are the most well known activators of CAR.…”

Molecular Cloning and Characterization of Bovine CYP26A1 Promoter

“…The DBD of RAR and/or RXR binds to the upstream sequences of RA responsive genes in the nucleus [5,7]. RA acts as a ligand to activate transcription of target genes by the binding of RAR/ RXR as a dimer to the specific sequences of DNA called retinoic acid response elements (RARE) [3,7,12].…”

“…spacer as the DR-5 or it contains a direct repeat of TGACCT (complementary sequence of AGGTCA) with a spacer of 5 bp as in the reverse orientation [3,5,7,12] (Fig. 1B).…”