Differential transactivation by orphan nuclear receptor NOR1 and its fusion gene product EWS/NOR1: possible involvement of poly(ADP-ribose) polymerase I, PARP-1

J Cell Biochem. 2008 Oct 15;105(3):785-800. doi: 10.1002/jcb.21876.


In extraskeletal myxoid chondrosarcoma, a chromosomal translocation creates a gene fusion between EWS and an orphan nuclear receptor, NOR1. The resulting fusion protein EWS/NOR1 has been believed to lead to malignant transformation by functioning as a transactivator for NOR1-target genes. By comparing the gene expression profiles of NOR1- and EWS/NOR1-overexpressing cells, we found that they largely shared up-regulated genes, but no significant correlation was observed with respect to the transactivation levels of each gene. In addition, the proteins associated with NOR1 and EWS/NOR1 were mostly the same in these cells. The results suggest that these proteins differentially transactivate overlapping target genes through a similar transcriptional machinery. To clarify the mechanisms underlying the transcriptional divergence between NOR1 and EWS/NOR1, we searched for alternatively associated proteins, and identified poly(ADP-ribose) polymerase I (PARP-1) as an NOR1-specific binding protein. Consistent with its binding properties, PARP-1 acted as a transcriptional repressor of NOR1, but not EWS/NOR1, in a luciferase reporter assay employing PARP-1(-/-) fibroblasts. Interestingly, suppressive activity of PARP-1 was observed in a DNA response element-specific manner, and in a subtype-specific manner toward the NR4A family (Nur77, Nurr1, and NOR1), suggesting that PARP-1 plays a role in the diversity of transcriptional regulation mediated by the NR4A family in normal cells. Altogether, our findings suggest that NOR1 and EWS/NOR1 regulate overlapping target genes differently by utilizing associated proteins, including PARP-1; and that EWS/NOR1 may acquire oncogenic activities by avoiding (or gaining) transcription factor-specific modulation by the associated proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Mice
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / metabolism*
  • RNA-Binding Protein EWS / genetics
  • RNA-Binding Protein EWS / metabolism
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism*
  • Receptors, Thyroid Hormone / genetics
  • Receptors, Thyroid Hormone / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transcriptional Activation / genetics*


  • DNA-Binding Proteins
  • EWS-NOR1 fusion protein, human
  • NR4A1 protein, human
  • NR4A2 protein, human
  • NR4A3 protein, human
  • Nr4a1 protein, mouse
  • Nr4a2 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Oncogene Proteins, Fusion
  • RNA-Binding Protein EWS
  • Receptors, Steroid
  • Receptors, Thyroid Hormone
  • Transcription Factors
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases