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

Abstract

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.

• Authors: Naganari Ohkura, Yuko Nagamura, Toshihiko Tsukada
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 105 Issue 3 Pg. 785-800 (Oct 15 2008) ISSN: 1097-4644 [Electronic] United States
• PMID: 18680143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• 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

Topics

• Animals
• COS Cells
• Chlorocebus aethiops
• DNA-Binding Proteins (genetics, 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, metabolism)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (metabolism)
• RNA-Binding Protein EWS (genetics, metabolism)
• Receptors, Steroid (genetics, metabolism)
• Receptors, Thyroid Hormone (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic
• Transcriptional Activation (genetics)