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Orphan Nuclear Receptor NOR-1 Enhances 3',5'-Cyclic Adenosine 5'-Monophosphate-Dependent Uncoupling Protein-1 Gene Transcription

Division of Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to:Sheila Collins, Division of Translational Biology, The Hamner Institutes for Health Sciences, Six Davis Drive, Research Triangle Park, North Carolina 27709. E-mail: scollins{at}thehamner.org.

Prolonged cold exposure induces nonshivering thermogenesis primarily through β-adrenergic- and cAMP-mediated regulation of uncoupling protein-1 (UCP1) in brown adipose tissue. Molecular mechanisms involved in this induction of Ucp1 gene transcription consists of an intricate interplay between many nuclear receptors in coordination with coactivators/corepressors. Recently, it has been shown that members of the nuclear receptor-4A (NR4A) family of orphan nuclear receptors (Nur77, Nurr1, and NOR-1) are highly responsive to cAMP-second messenger pathways. Here we have identified a new regulatory motif in the Ucp1 promoter that binds NR4As to stimulate Ucp1 gene transcription. Upon cold exposure of mice, or β-agonist treatment of mouse and human adipocytes, the expression of NR4A nuclear receptors is rapidly induced, with NOR-1 being the most robust, and this precedes increases in Ucp1 expression. A dominant-negative mutant Nur-77 receptor that prevents the transcriptional activity of NR4A receptors blocked β-adrenergic receptor-stimulated Ucp1 gene transcription. By gel shift and chromatin immunoprecipitation assays, we defined the sequence (–5.64 kb) in the Ucp1 promoter to which NOR-1 binds. In transient reporter assays, this element significantly augments the activity of a 3.7-kb Ucp1 promoter. These results extend our understanding of the combinatorial complexity in the signaling pathways that control this tissue-specific gene.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARγ  |  RXRα  |  NGFIB  |  NURR1  |  NOR1

Coregulators:   PGC-1

Ligands:   Rosiglitazone

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