The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-activation, Coactivator Recruitment, and Activation by the Purine Anti-metabolite 6-Mercaptopurine

Abayratna Wansa, S., Harris, J., Yan, G., Ordentlich, P. and Muscat, G. E. (2003) The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-activation, Coactivator Recruitment, and Activation by the Purine Anti-metabolite 6-Mercaptopurine. Journal of Biological Chemistry, 278 27: 24776-24790. doi:10.1074/jbc.M300088200

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Author Abayratna Wansa, S.
Harris, J.
Yan, G.
Ordentlich, P.
Muscat, G. E.
Title The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-activation, Coactivator Recruitment, and Activation by the Purine Anti-metabolite 6-Mercaptopurine
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2003-07-04
Sub-type Article (original research)
DOI 10.1074/jbc.M300088200
Open Access Status File (Publisher version)
Volume 278
Issue 27
Start page 24776
End page 24790
Total pages 15
Editor Herbet Tabor
Place of publication Bethesda, USA
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2003
Language eng
Subject C1
270104 Membrane Biology
730108 Cancer and related disorders
Abstract 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.
Keyword Pituitary-adrenal Axis
Ligand-binding Domain
Serum Growth-factors
T-cell Apoptosis
Ngfi-b
Muscle Differentiation
Steroid-receptor
Gene-expression
Transcriptional Activity
Nurr1/nur77 Subfamily
Q-Index Code C1

 
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Created: Wed, 15 Aug 2007, 01:46:18 EST