Disease relevance of NR5A2

• The human homologue of the Drosophila melanogaster orphan nuclear receptor fushi tarazu factor 1 (Ftz-F1), NR5A2 (hB1F), was initially identified as a regulatory factor that binds and activates enhancer II of hepatitis B virus [1].
• In this report, a bacterial artificial chromosome clone and several phage clones covering the NR5A2 (hB1F) gene were isolated and the complete genomic sequence was obtained [1].
• In order to identify critical factors stimulating LRH-1 expression leading to deregulated cellular proliferation, we studied its expression and its regulation in several breast cancer cell lines [2].
• Finally, LRH-1 protein expression was detected by immunohistochemistry in tumor cells of human mammary ductal carcinomas [2].
• Adenovirus mediated overexpression of LRH-1 or SF-1 had qualitatively similar effects [3].

Psychiatry related information on NR5A2

• The domains included in the FTF were motor skills, executive functions, perception, memory, language, social skills and learning, in addition to a domain for emotional and behavioural problems [4].
• The FTF and the Child Behavior Checklist (CBCL) were sent to the parents of the children together with questions about background conditions [5].
• The Five to Fifteen parent questionnaire (FTF) was developed to offer a neuropsychological dimension to the assessment of children with Attention Deficit/Hyperactivity Disorder and other child psychiatric disorders [4].

High impact information on NR5A2

• The third component is a factor (cleavage and polyadenylation factor, CPF) that is needed for the cleavage reaction and, in addition, confers specificity to the poly(A) polymerase activity; the native molecular weight of CPF is approximately 200 kd [6].
• Poly(A) polymerase together with CPF is sufficient to specifically polyadenylate pre-mRNA substrates that have been precleaved at the poly(A) addition site [6].
• One CPF isomer, CPF(DD), preserved CD4-dependent T cell function while inhibiting HIV-1 infection of H9 tumor cells and human T cells [7].
• In these tissues, LRH-1 plays a predominant role in development, reverse cholesterol transport, bile-acid homeostasis and steroidogenesis [8].
• LRH-1 is expressed in tissues derived from endoderm, including intestine, liver and exocrine pancreas, as well as in the ovary [8].

Chemical compound and disease context of NR5A2

• Transfections in HepG2, Hep3B, and PLC/PRF/5 hepatoma cells using chloramphenicol acetyltransferase reporter genes with the nucleocapsid promoter linked or not linked to enhancer I indicate that FTF is a potent activator of the HBV core promoter, more efficient than HNF4alpha, HNF3alpha, HNF3beta, or C/EBPalpha [9].

Biological context of NR5A2

• In this study, we have identified and characterized the homeodomain protein Prox1 as a co-repressor for liver receptor homologue 1 (LRH1/NR5A2), a master regulator of cholesterol homeostasis in mammals [10].
• Thus, this study is the first to report the concomitant regulation of SF-1 in theca interna and granulosa cells throughout the ovulation/luteinization process, and to demonstrate the novel expression and hormonal regulation of NR5A2 in ovarian cells [11].
• The transcription start site of the NR5A2 (hB1F) gene was mapped downstream of a canonical TATA box [1].
• Alignment of different cDNAs of the NR5A2 (hB1F) gene with the genomic sequence facilitated the delineation of its structural organization, which spans over 150 kb and consists of eight exons interrupted by seven introns [1].
• However, the relative ability of these mutants to inhibit LRH-1-mediated transactivation was markedly decreased [12].

Anatomical context of NR5A2

• In contrast, the granulosa cell layer was the predominant, if not the sole, site of NR5A2 mRNA expression in the follicle [11].
• In situ hybridization and gene expression studies demonstrate that both LRH-1 and CEL are co-expressed and confined to the exocrine pancreas [13].
• LRH-1 expression was higher in CL, compared with mature ovarian follicles [14].
• In liver cells, 5a increased the expression of the LRH-1 target gene small heterodimer partner (SHP) [15].
• To test this hypothesis, LRH-1 expression in human adult and fetal adrenal glands was examined by RT-PCR analysis [16].

Associations of NR5A2 with chemical compounds

• Interestingly, NR5A2 was found to be, by far, the major NR5A subfamily member expressed in the preovulatory follicle and the corpus luteum [11].
• In the current study we test the hypothesis that liver receptor homologue-1 (LRH; designated NR5A2) is involved in the regulation of steroid hormone production [17].
• Both SHP proteins specifically interact with the AF-2 transactivation domain of LRH-1 both in vivo and in vitro [12].
• Interestingly, siRNA-mediated inactivation of LRH-1 decreased the E2-dependent proliferation of MCF7 cells [2].
• LRH-1 did not augment FSH-stimulated estrogen production, whereas SF-1 produced only a slight ( approximately 30%) augmentation of FSH-stimulated estrogen production [3].

Physical interactions of NR5A2

• Gel shift assays reveal that Prox1 impairs the binding of hLRH-1 to the promoter of human cyp7a1 gene [18].
• We present the crystal structure at a resolution of 1.9 A of the ligand-binding domain of hLRH-1 in complex with the NR box 1 motif of human SHP, which we find contacts the AF-2 region of hLRH-1 using selective structural motifs [19].
• When recombinant MBF2 was added to the HeLa cell nuclear extract in the presence of MBF1 and FTZ622 bearing the DNA-binding region of FTZ-F1, it selectively activated transcription of the fushi tarazu gene [20].

Regulatory relationships of NR5A2

• Altogether, these data demonstrate that LRH-1 is transcriptionally regulated by the ER alpha and reinforce the hypothesis that LRH-1 could exert potential oncogenic effects during breast cancer formation [2].
• Dosage-sensitive sex-reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene-1 inhibited LRH-1 stimulated CYP11A1 expression, and that was not overcome by the presence of PKA agonist [21].
• DAX-1 inhibited LRH-1-stimulated HSD3B2, which was maintained in the presence of dibutyryl cAMP [14].
• Liver receptor homolog 1 controls the expression of carboxyl ester lipase [13].
• LRH-1 significantly induced StAR promoter activity in a concentration-dependent manner [22].
• It was confirmed that suppression in endogenous LRH-1 by small interference RNA stimulates the mRNA levels of certain SREBP target genes and that elevation in active SREBPs in the nucleus in response to cholesterol depletion suppresses the LRH-1 activity [23].
• We demonstrate that bile acids suppress APOM expression in a SHP-dependent manner in vitro and in vivo by inhibiting LRH-1 transcriptional activity on the APOM promoter as demonstrated by in vivo ChIP assay [24].

Other interactions of NR5A2

• In hLRH-1 LBD, helices 2 and 10 are essential for Prox1 recruitment [18].
• The nuclear receptor liver receptor homolog-1 is an estrogen receptor target gene [2].
• In this study, we examined the role of LRH-1 in the regulation of human granulosa cell CYP11A1 expression [21].
• Liver receptor homolog-1 and steroidogenic factor-1 have similar actions on rat granulosa cell steroidogenesis [3].
• Cell transfection, mutation analysis, and EMSA were performed to examine the role of LRH-1 in the regulation of HSD3B2 [14].

Analytical, diagnostic and therapeutic context of NR5A2

• Northern blot analysis revealed that SF-1 and NR5A2 were expressed in all major steroidogenic tissues, with the exception that NR5A2 was not present in the adrenal [11].
• Using a semiquantitative RT-PCR/Southern blotting approach, the regulation of SF-1 and NR5A2 mRNAs in vivo was studied in equine follicular cells obtained from preovulatory follicles isolated between 0 and 39 h post hCG [11].
• This transcriptional regulation was the result of a direct binding of the ER to the LRH-1 promoter, as demonstrated by gelshift and chromatin immunoprecipitation assays [2].
• In MCF7, LRH-1 expression was highly induced after treatment with 17beta-estradiol (E2) [2].
• Electrophoretic mobility shift assay identified an overlapping HNF4alpha- and CPF-binding site in the +198/+227 region [25].

References