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Matches in Nanopublications for { <http://www.tkuhn.ch/bel2nanopub/RALb8wfaM-mn-5ZKEUESwkKpLl4uRFK_drZuSRGsDyTPs#_5> ?p ?o ?g. }

• _5 value "NOR-1/NR4A3 is an \"orphan member\" of the nuclear hormone receptor superfamily. NOR-1 and its close relatives Nurr1 and Nur77 are members of the NR4A subgroup of nuclear receptors. Members of the NR4A subgroup are induced through multiple signal transduction pathways. They have been implicated in cell proliferation, differentiation, T-cell apoptosis, chondrosarcomas, neurological disorders, inflammation, and atherogenesis. However, the mechanism of transcriptional activation, coactivator recruitment, and agonist-mediated activation remain obscure. Hence, we examined the molecular basis of NOR-1-mediated activation. We observed that NOR-1 trans-activates gene expression in a cell- and target-specific manner; moreover, it operates in an activation function (AF)-1-dependent manner. The N-terminal AF-1 domain delimited to between amino acids 1 and 112, preferentially recruits the steroid receptor coactivator (SRC). Furthermore, SRC-2 modulates the activity of the AF-1 domain but not the C-terminal ligand binding domain (LBD). Homology modeling indicated that the NOR-1 LBD was substantially different from that of hRORbeta, a closely related AF-2-dependent receptor. In particular, the hydrophobic cleft characteristic of nuclear receptors was replaced with a very hydrophilic surface with a distinct topology. This observation may account for the inability of this nuclear receptor LBD to efficiently mediate cofactor recruitment and transcriptional activation. In contrast, the N-terminal AF-1 is necessary for cofactor recruitment and can independently conscript coactivators. Finally, we demonstrate that the purine anti-metabolite 6-mercaptopurine, a widely used antineoplastic and anti-inflammatory drug, activates NOR-1 in an AF-1-dependent manner. Additional 6-mercaptopurine analogs all efficiently activated NOR-1, suggesting that the signaling pathways that modulate proliferation via inhibition of de novo purine and/or nucleic acid biosynthesis are involved in the regulation NR4A activity. We hypothesize that the NR4A subgroup mediates the genotoxic stress response and suggest that this subgroup may function as sensors that respond to genotoxicity. TEXT fROM PAPER The NR4A family members can bind as monomers and homodimers to single/tandem copies of the nerve growth factor-inducible response element (NBRE), AAAGGTCA, a variant NR half-site, and constitutively regulate transcription. In addition to binding DNA as monomers, Nur77 and Nurr1 (but not NOR1) heterodimerize with RXR and mediate efficient trans-activation in response to RXR-specific agonists from DR5 motifs. Moreover, a Nur response element has been found in the promoter region of the pro-opiomelanocortin gene (POMC) that is efficiently bound and transactivated by Nur and NOR1 homodimers (3-8). " provenance.
• _5 wasQuotedFrom 12709428 provenance.