The EWSRI/NR4A3 fusion protein of extraskeletal myxoid chondrosarcoma activates the PPARG nuclear receptor gene Journal Article


Authors: Filion, C.; Motoi, T.; Olshen, A. B.; Lae, M.; Emnett, R. J.; Gutmann, D. H.; Perry, A.; Ladanyi, M.; Labelle, Y.
Article Title: The EWSRI/NR4A3 fusion protein of extraskeletal myxoid chondrosarcoma activates the PPARG nuclear receptor gene
Abstract: The NR4A3 nuclear receptor is implicated in the development of extraskeletal myxoid chondrosarcoma (EMC), primitive sarcoma unrelated to conventional chondrosarcomas, through a specific fusion with EWSR1 resulting in an aberrant fusion protein that is thought to disrupt the transcriptional regulation of specific target genes. We performed an expression microarray analysis of EMC tumours expressing the EWSR1/NR4A3 fusion protein, comparing their expression profiles to those of other sarcoma types. We thereby identified a set of genes significantly overexpressed in EMC relative to other sarcomas, including PPARG and NDRG2. Western blot or immunohistochemical analyses confirm that PPARG and NDRG2 are expressed in tumours positive for EWSR1/NR4A3. Bioinformatic analysis identified a DNA response element for EWSR1/NR4A3 in the PPARG promoter, andband-shift experiments and transient transfections indicate that EWSR1/NR4A3 can activate transcription through this element. Western blots further show that an isoform of the native NR4A3 receptor lacking the C-terminal domain is very highly expressed in tumours positive for EWSR1/NR4A3, and co-transfections of this isoform along with EWSR1/NR4A3 indicate that it may negatively regulate the activity of the fusion protein on the PPARG promoter. These results suggest that the overall expression of PPARG in EMC may be regulated inpart by the balance between EWSR1/NR4A3 and NR4A3, and that PPARG may play a crucial role in the development of these tumours. The specific up-regulation of PPARG by EWSR1/NR4A3 may also have potential therapeutic implications. Copyright © 2008 Pathological Society of Great Britain and Ireland.
Keywords: immunohistochemistry; controlled study; protein expression; unclassified drug; dna binding protein; oncoprotein; genetics; dna-binding proteins; nonhuman; molecular genetics; methodology; protein domain; protein function; animal cell; metabolism; reverse transcription polymerase chain reaction; gene expression profiling; transcription initiation; neoplasm proteins; protein serine threonine kinase; physiology; rna binding protein; rna; rna-binding proteins; biosynthesis; amino acid sequence; molecular sequence data; hybrid protein; messenger rna; reverse transcriptase polymerase chain reaction; rna, messenger; microarray analysis; oligonucleotide array sequence analysis; protein-serine-threonine kinases; tumor protein; rat; western blotting; oncogene proteins, fusion; target genes; dna microarray; bioinformatics; dna responsive element; gel mobility shift assay; chromosomal translocations; ewsr1/nr4a3; extraskeletal myxoid chondrosarcoma; fusion proteins; nuclear receptors; pparg; peroxisome proliferator activated receptor gamma; protein ewsr1; protein ndrg2; protein nr4a3; serum and glucocorticoid regulated kinase 1; calmodulin binding protein; ewsr1 protein, human; immediate early protein; nr4a3 protein, human; serum glucocorticoid regulated kinase; serum-glucocorticoid regulated kinase; steroid receptor; thyroid hormone receptor; chondrosarcoma; transient transfection; calmodulin-binding proteins; electrophoretic mobility shift assay; immediate-early proteins; ppar gamma; receptors, steroid; receptors, thyroid hormone; rna, neoplasm; transcriptional activation
Journal Title: Journal of Pathology
Volume: 217
Issue: 1
ISSN: 0022-3417
Publisher: Wiley Blackwell  
Date Published: 2009-01-01
Start Page: 83
End Page: 93
Language: English
DOI: 10.1002/path.2445
PUBMED: 18855877
PROVIDER: scopus
PMCID: PMC4429309
DOI/URL:
Notes: --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "CODEN: JPTLA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Marick E. Lae
    15 Lae
  2. Toru Motoi
    16 Motoi
  3. Marc Ladanyi
    870 Ladanyi
  4. Adam B Olshen
    107 Olshen