Defining an N-terminal activation domain of the orphan nuclear receptor Nurr1.
Nurr1 is an orphan nuclear receptor essential for the development of midbrain dopaminergic neurons. Activation of Nurr1 depends on two so-called activation functions (AFs) situated in the N- and C-terminal regions, respectively. The region important for activation within the C-terminal domain has been shown to promote activation in a highly cell-type specific fashion in the absence of added exogenous ligands. In contrast, the region in the N-terminal domain (AF1) has been much less characterized. Here we mutagenized the N-terminal domain of Nurr1 to define essential activation regions. The results identified a short core activation region localized close to the N-terminus of Nurr1. In addition, cell-type specific influences by other signaling pathways were analyzed by mutagenesis of specific conserved phosphorylation sites. The results indicate that mitogen-activated protein kinase activity (MAPK) positively influences Nurr1 AF1-dependent transcriptional activation via a conserved phosphorylation site outside the core activation region.
Nordzell
Mariette
M
Ludwig Institute for Cancer Research, Stockholm Branch, Box 240, Stockholm S-171 77, Sweden.
Aarnisalo
Piia
P
Benoit
Gérard
G
Castro
Diogo S
DS
Perlmann
Thomas
T
D000595:Amino Acid Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010957:Plasmids / Q000235:genetics; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; D004247:DNA; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D001616:beta-Galactosidase; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one