Disease relevance of NR1D1

• Correlation between long-term survival in breast cancer patients and amplification of two putative oncogene-coamplification units: hst-1/int-2 and c-erbB-2/ear-1 [1].
• Amplification of c-erbB-2 and/or ear-1 was strongly correlated with poor prognosis in all 176 patients, especially those with lymph node metastasis [1].
• Functional characterization of an orphan nuclear receptor, Rev-ErbAalpha, in chondrocytes and its potential role in osteoarthritis [2].
• Gene mapping in extended families with inherited, early-onset breast and ovarian cancer indicates that BRCA1 is distal to THRA1 and proximal to D17S183 (SCG43), an interval of < 4 cM [3].
• Since thyroid hormones are known to stimulate bone resorption, the THRA1 gene might be involved in the etiology and pathogenesis of van Buchem disease [4].

High impact information on NR1D1

• Two erbA homologs, termed ear-1 and ear-7, are present in the human genome on chromosome 17 [5].
• The corresponding PLA2 gene is revealed to be an orthologue of terminal ear1, a maize (Zea mays) gene that encodes a MEI2-like RNA binding protein [6].
• Interestingly, the only marker not showing recombination with the disease locus was an intragenic marker of the thyroid-hormone receptor alpha1 (THRA1) gene, which generated a LOD score of 12.84 at straight theta=.00 [4].
• In order to pinpoint the locale of the gene for early-onset familial breast and ovarian cancer (BRCA1), polymorphisms were developed within the locus for thyroid hormone receptor alpha (THRA1) and for several anonymous sequences at chromosome 17q12-q21 [3].
• The THRA1 polymorphism is a dinucleotide repeat with 10 alleles and heterozygosity.79 [3].

Biological context of NR1D1

• The conservation of the bidirectionally transcribed regions of c-erbA alpha-2 and Rev-ErbA alpha in human and rat suggests that this unusual genomic arrangement has an important function, perhaps related to the regulation of gene expression [7].
• It was hypothesized that base pairing with Rev-ErbA alpha blocks splicing of alpha 2 mRNA, thereby favoring formation of the non-overlapping alpha 1 [8].
• This investigation utilised the mammalian two hybrid system and transfection analysis to demonstrate that Rev-erbA alpha and RVR will not efficiently interact with either ID-I or ID-II separately from RIP13a or RIP13delta1 [9].
• Dinucleotide repeat polymorphism in the human thyroid hormone receptor alpha gene (THRA1) on chromosome 17 [10].
• This rearrangement represented a deletion of exons 8-10 of one THRA1 allele that was also coamplified with ERBB2 [11].

Anatomical context of NR1D1

• Rev-Erbalpha (NR1D1) is an orphan nuclear receptor encoded on the opposite strand of the thyroid receptor alpha gene [12].
• A cDNA encoding Rev-ErbA alpha, a member of the thyroid/steroid hormone receptor superfamily, has been isolated from a human fetal skeletal muscle library [7].
• Southern analysis revealed a rearrangement of THRA1 in the BT474 breast cancer cell line [11].
• We also demonstrated that modulation of Rev-ErbAalpha expression in chondrocytes may be a novel means of regulating the expression and production of multiple matrix-degrading enzymes [2].
• OBJECTIVE: To evaluate the expression and function of the orphan nuclear receptor Rev-ErbAalpha in articular cartilage and to investigate its role in osteoarthritis (OA) [2].

Associations of NR1D1 with chemical compounds

• The phenylalanine residues, F402 and F441, in RVR and Rev-erbA alpha, respectively, were critical residues in supporting corepressor interaction [13].
• Isolation of a cDNA encoding human Rev-ErbA alpha: transcription from the noncoding DNA strand of a thyroid hormone receptor gene results in a related protein that does not bind thyroid hormone [7].
• The interaction of NR2E3 with NR1D1 was confirmed by glutathione S-transferase pulldown and co-immunoprecipitation experiments [14].
• Utilising mammalian two hybrid technology, we have also demonstrated that Rev-erbA alpha does not associate with the interaction domain (aa 2218-2451) of the nuclear receptor corepressor, N-CoR, that is known to interact with the thyroid hormone and retinoic acid receptors [15].
• The activity of this human THRA promoter is enhanced by the synthetic glucocorticoid dexamethasone but seems unaffected by thyroid hormones [16].

Other interactions of NR1D1

• Identification and characterization of a novel corepressor interaction region in RVR and Rev-erbA alpha [13].
• ROR(alpha) (NR1F1) and Reverb(alpha) (NR1D1) are two members of this family whose biological functions are largely unknown [17].
• In conclusion, these data from two independent approaches demonstrate that repression by Rev-erbA alpha and RVR is mediated by an interaction of ID-I and ID-II of N-CoR, RIP13a and delta1 with the putative ligand binding domain of the orphan receptors [9].
• Because all three genes hybridized to DNA fragments of different lengths it seems unlikely that the gene for 17-HSD is located very close to THRA1 and ERBB2 [18].
• METHODS: Expression of Rev-ErbAalpha was analyzed at both the messenger RNA and protein levels in human and bovine articular cartilage and chondrocytes by real-time polymerase chain reaction (TaqMan) and immunocytochemical techniques [2].

Analytical, diagnostic and therapeutic context of NR1D1

• THRA1 and ERBB2 (both reported to be located in this region of chromosome 17) was performed by pulsed-field gel electrophoresis (PFGE) using several rare-cutting restriction endonucleases [18].
• These results therefore identified 3 B-cell EA-R epitopes which might be potentially useful for clinical or epidemiological studies of EBV-associated lymphoproliferative diseases [19].
• Here, we have carried out a case-control study to investigate whether there is an association between THRA1 CA repeat or BAT-40 A repeat polymorphisms and thyroid cancer risk [20].
• Using degenerate primers, one unique tel (terminal ear1-like) gene from seven Poaceae members, covering almost all the phylogenetic tree of the family, was identified by PCR [21].
• Prenatal diagnosis of Glanzmann thrombasthenia using the polymorphic markers BRCA1 and THRA1 on chromosome 17 [22].

References