Defining an N-terminal activation domain of the orphan nuclear receptor Nurr1

Biochem Biophys Res Commun. 2004 Jan 2;313(1):205-11. doi: 10.1016/j.bbrc.2003.11.079.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Cell Nucleus / metabolism
  • DNA / metabolism
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Genes, Reporter / genetics
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Plasmids / genetics
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation
  • Transfection
  • beta-Galactosidase / genetics
  • beta-Galactosidase / metabolism

Substances

  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Flavonoids
  • NR4A2 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Transcription Factors
  • DNA
  • Luciferases
  • Mitogen-Activated Protein Kinases
  • beta-Galactosidase
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one