NOR‐2 (neuron‐derived orphan receptor), a brain zinc finger protein, is highly induced during liver regeneration

Studies in Nur77-deficient mice have shown that the basal regulation of hypothalamic and pituitary functions as well as the adrenocortical steroidogenesis in these animals is normal. This indicates that Nur77-related orphan receptors may substitute Nur77 functions in the hypothalamo-pituitary-adrenal axis by a compensatory mechanism. Nor1 is the most recently cloned member of the NGFI-B/Nur77 subfamily, and its properties are still largely unknown. We demonstrate here that Nor1 is expressed in the pituitary gland and adrenal cortex, and that ACTH and angiotensin II (AngII) treatment of adrenal fasciculata cells induces Nor1 expression. Time-course analysis with both hormones on steroidogenic capacity and the specific gene expression in adrenal cells strongly suggest that Nor1 is an intermediate in the long-term consequences of ACTH or AngII treatment. The Nor1 and NGFI-B/Nur77 amino acid sequence homology and the analysis of the trans-activation properties of Nor1 show that the overall structural and functional organization of the two proteins is similar. As observed with NGFI-B/Nur77, Nor1 activates the expression of genes encoding steroidogenic enzymes as P450c21, through its interaction with NGFI-B response element promoter sequences. In contrast, binding experiments of Nor1 with the palindromic NurRE sequence suggest that Nor1 is not an efficient substitute for the NGFI-B/Nur77 activation of the POMC gene expression in pituitary glands. All these results indicate that Nor1 and NGFI-B/Nur77 may play similar albeit distinct roles in the hypothalamo-pituitary-adrenal axis. Further experiments also show that the mechanisms responsible for the transcriptional regulation of Nor1 in adrenal cells appear to depend on the protein kinase A and protein kinase C cascades.

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“…in the Y1 cell line, as NBRE was previously reported to be a specific DNA-binding site for the protein (1,23). The data in Fig.…”

Section: Nor1 Amino-and Carboxyl-terminus Are Important For Transcripsupporting

confidence: 62%

Nuclear Receptors Nor1 and NGFI-B/Nur77 Play Similar, Albeit Distinct, Roles in the Hypothalamo-Pituitary-Adrenal Axis¹

et al. 2000

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“…Two additional mRNA variants of the CHN gene have been identified, both of which are gen- (Labelle et al, 1995;Clark et al, 1996;Brody et al, 1997;Antonescu et al, 1998;Attwooll et al, 1999;Panagopoulos et al, 1999;Sjö gren et al, 1999;Okamoto et al, 2001;this study) erated by alternative splicing. CHN, like Nurr1 and NGFI-B, is classified as an immediate-early response protein, is induced by various stimuli in cultured cells, is implicated in liver regeneration, and has been suggested to be involved in neural development (Ohkura et al, 1994(Ohkura et al, , 1996a(Ohkura et al, ,b, 1998Petropoulos et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma

Panagopoulos

Mertens

Isaksson

et al. 2002

Genes Chromosomes & Cancer

108

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Extraskeletal myxoid chondrosarcoma (EMC) is a soft-tissue neoplasm cytogenetically characterized by the translocations t(9;22)(q22;q11-12) or t(9;17)(q22;q11), generating EWS/CHN or RBP56/CHN fusion genes, respectively. In the present study, 18 EMCs were studied both cytogenetically and at the molecular level. Chromosomal aberrations were detected in 16 samples: 13 with involvement of 9q22 and 22q11-12, and three with rearrangements of 9q22 and 17q11. Fifteen cases had an EWS/CHN fusion transcript and three had an RBP56/CHN transcript. The most frequent EWS/CHN transcript (type 1; 10 tumors), involved fusion of EWS exon 12 with CHN exon 3, and the second most common (type 5; two cases) was fusion of EWS exon 13 with CHN exon 3. In all tumors with RBP56/CHN fusion, exon 6 of RBP56 was fused to exon 3 of CHN. By genomic XL PCR and sequence analyses, the breakpoints from 14 cases were mapped in the EWS, RBP56, and CHN genes. In CHN, 12 breakpoints were found in intron 2 and only two in intron 1. In EWS, the breaks occurred in introns 7 (one break), 12 (eight breaks), and 13 (one break), and in RBP56 in intron 6. Repetitive elements such as Alu and LINE sequences seem to have limited, if any, importance in the genesis of EWS/CHN and RBP56/CHN chimeras. Furthermore, there were no chi, chi-like, topoisomerase II, or translin consensus sequences in the introns harboring the translocation breakpoints, nor could the number of topo I sites in EWS, RBP56, and CHN introns explain the uneven distribution of the breakpoints among EWS or CHN introns. Additional genetic events, such as nucleotide insertions, homologies at the junction, deletions, duplications, and inversions, were found to accompany the translocations, indicating that the chromosomal translocations do not require sequence-specific recombinases or extensive homology between the recombined sequences.

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“…NOR-2 has so far been found in humans [Ohkura et al, 1998], rat [Petropoulos et al, 1995] and mouse [Maltais and Labelle, 2000]. The full-length hNOR-1 is 626 amino acids long, while hNOR-2 only contains 443 amino acids.…”

Section: The Occurrence Of C-terminal Splice Variants Of Nuclear Recementioning

confidence: 99%

“…Rat NOR-2 [Petropoulos et al, 1995] and hDAX-1α [Hossain et al, 2004] bind to their response element with the same affinity as their cognate canonical receptor in gel shift assays. Other splice variants show significantly reduced DNA binding in vitro (hERβcx [Moore et al, 1998; Ogawa et al, 1998], hGRβ [Oakley et al, 1999], hTRα2 [Hermann et al, 1991; Katz and Lazar, 1993], hγORF4 [Kim et al, 2006], mNurr2 [Ohkura et al, 1999]), or do not bind to their response elements at all (hPPARα tr [Gervois et al, 1999], mCAR2 [Choi et al, 1997], and hCAR(sv5) [Arnold et al, 2004]).…”

Section: The Function Of C-terminal Splice Variants Of Nuclear Receptorsmentioning

confidence: 99%

Naturally occurring C-terminal splice variants of nuclear receptors

Vaart

Schaaf

2009

Nucl Recept Signal

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Alternative mRNA splicing in the region encoding the C-terminus of nuclear receptors results in receptor variants lacking the entire ligand-binding domain (LBD), or a part of it, and instead contain a sequence of splice variant-specific C-terminal amino acids. A total of thirteen such splice variants have been shown to occur in vertebrates, and at least nine occur in humans. None of these receptor variants appear to be able to bind endogenous ligands and to induce transcription on promoters containing the response element for the respective canonical receptor variant. Interestingly, ten of these C-terminal splice variants have been shown to display dominant-negative activity on the transactivational properties of their canonical equivalent. Research on most of these splice variants has been limited, and the dominant-negative effect of these receptor variants has only been demonstrated in reporter assays in vitro, using transiently transfected receptors and reporter constructs. Therefore, the in vivo function and relevance of most C-terminal splice variants remains unclear. By reviewing the literature on the human glucocorticoid receptor β-isoform (hGRβ), we show that the dominant-negative effect of hGRβ is well established using more physiologically relevant readouts. The hGR β-isoform may alter gene transcription independent from the canonical receptor and increased hGRβ levels correlate with glucocorticoid resistance and the occurrence of several immune-related diseases. Thus, available data suggests that C-terminal splice variants of nuclear receptors act as dominant-negative inhibitors of receptor-mediated signaling in vivo, and that aberrant expression of these isoforms may be involved in the pathogenesis of a variety of diseases.

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NOR‐2 (neuron‐derived orphan receptor), a brain zinc finger protein, is highly induced during liver regeneration

Cited by 20 publications

References 27 publications

Nuclear Receptors Nor1 and NGFI-B/Nur77 Play Similar, Albeit Distinct, Roles in the Hypothalamo-Pituitary-Adrenal Axis¹

Nuclear Receptors Nor1 and NGFI-B/Nur77 Play Similar, Albeit Distinct, Roles in the Hypothalamo-Pituitary-Adrenal Axis¹

Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma

Naturally occurring C-terminal splice variants of nuclear receptors

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NOR‐2 (neuron‐derived orphan receptor), a brain zinc finger protein, is highly induced during liver regeneration

Cited by 20 publications

References 27 publications

Nuclear Receptors Nor1 and NGFI-B/Nur77 Play Similar, Albeit Distinct, Roles in the Hypothalamo-Pituitary-Adrenal Axis1

Nuclear Receptors Nor1 and NGFI-B/Nur77 Play Similar, Albeit Distinct, Roles in the Hypothalamo-Pituitary-Adrenal Axis1

Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma

Naturally occurring C-terminal splice variants of nuclear receptors

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Product

Resources

About

Nuclear Receptors Nor1 and NGFI-B/Nur77 Play Similar, Albeit Distinct, Roles in the Hypothalamo-Pituitary-Adrenal Axis¹

Nuclear Receptors Nor1 and NGFI-B/Nur77 Play Similar, Albeit Distinct, Roles in the Hypothalamo-Pituitary-Adrenal Axis¹