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Characterization of a new brain-specific isoform of the EWS oncoprotein
T Melot1, L Dauphinot, N Sévenet
1Laboratoire de Pathologie Moléculaire des Cancers, INSERM U509, Paris, France.
Abstract:
EWS and related TAFII68 and TLS/FUS genes are fused with different genes encoding transcription factors in various human cancers. The products of these genes have the ability to bind RNA and have been shown to be part of splicing and transcription complexes. We show that the EWS, TAFII68 and TLS/FUS proteins are expressed to various levels in all adult murine tissues. We characterize a new isoform of EWS that is specifically expressed in the central nervous system, in both mice and humans. It is shown to be related to a splice variant which includes a new 18-bp exon, termed 4', between exon 4 and 5. The detection of this isoform in spontaneously differentiating SH-SY5Y neuroblastoma cells and in nerve growth factor-induced PC12 cells further links this isoform to neural differentiation. RT-PCR experiments indicate that the level of expression of the brain-specific EWS isoform is stable during brain development whereas that of the ubiquitous EWS isoform decreases during this period. The two isoforms show a parallel decrease in expression after birth. The 4' exon is not detected in tumour-specific EWS fusion transcripts, suggesting that its presence may impair their oncogenic properties. Interestingly, sequences of the 4' exon and flanking regions show remarkable similarities to that of the neural-specific c-src exon, suggesting common mechanisms for the alternative splicing of these exons. The phylogenetic conservation and relationship to neural differentiation strongly suggests an important functional role for this exon.
Insights
A novel brain-specific isoform of the EWS gene was identified, linked to neural differentiation. Its absence in cancer fusions suggests a role in preventing oncogenesis.
Area of Science:
- Molecular biology
- Neuroscience
- Oncology
Background:
- The EWS gene and related genes (TAFII68, TLS/FUS) are implicated in human cancers through fusion with transcription factors.
- These fusion proteins interact with RNA and are involved in splicing and transcription complexes.
Purpose of the Study:
- To characterize the expression and function of EWS protein isoforms in various tissues.
- To identify and analyze a novel, brain-specific EWS isoform and its potential role in neural differentiation and oncogenesis.
Main Methods:
- Reverse transcription polymerase chain reaction (RT-PCR) to analyze gene expression.
- Characterization of splice variants and protein isoforms.
- Comparison of exon sequences and phylogenetic analysis.
Main Results:
- EWS, TAFII68, and TLS/FUS proteins are expressed in adult murine tissues.
- A new EWS isoform, containing an 18-bp exon (4'), is specifically expressed in the central nervous system (CNS) of mice and humans.
- This CNS isoform is linked to neural differentiation and its expression is stable during brain development, unlike the ubiquitous isoform.
- The 4' exon is absent in tumor-specific EWS fusion transcripts, potentially inhibiting oncogenic activity.
- The 4' exon shares sequence similarities with neural-specific c-src exon, suggesting conserved alternative splicing mechanisms.
Conclusions:
- A novel EWS isoform with a specific role in neural differentiation has been identified.
- The absence of the 4' exon in EWS fusion transcripts may contribute to cancer development.
- The findings suggest conserved mechanisms for alternative splicing in neural development and highlight a potential functional role for the 4' exon in regulating EWS protein activity.
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