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Coupled alteration of transcription and splicing by a single oncogene: boosting the effect on cyclin D1 activity

Gabriel Sanchez1, Olivier Delattre, Didier Auboeuf

  • 1INSERM U685, Institut Universitaire d'Hématologie, Paris, France.

Cell Cycle (Georgetown, Tex.)
|August 5, 2008
PubMed

Insights

Altered gene regulation in cancer, specifically the EWS protein in Ewing sarcoma, can change RNA splicing. This leads to increased production of the oncogenic cyclin D1b splice variant, promoting cancer cell growth.

Area of Science:

  • Molecular biology
  • Cancer research
  • Gene regulation

Background:

  • Cancer cells exhibit altered gene expression, including changes in transcription and mRNA splicing.
  • Aberrant splicing variants are frequently associated with cancer development and progression.
  • Transcriptional coregulators, such as the proto-oncogene EWS, are implicated in splicing regulation and are often altered in cancer.

Purpose of the Study:

  • To investigate the link between alterations in transcriptional regulators and aberrant mRNA splicing in cancer.
  • To explore the role of EWS alteration in Ewing sarcoma and its impact on CCND1 gene expression and splicing.
  • To discuss the broader implications of transcriptional dysregulation in driving splicing alterations in various cancers.

Main Methods:

  • Analysis of RNA polymerase II dynamics over the CCND1 proto-oncogene.
  • Assessment of transcription and splicing alterations in Ewing sarcoma cells.
  • Review of existing data on transcriptional coregulators and splicing in cancer.

Main Results:

  • Alteration of EWS in Ewing sarcoma modifies RNA polymerase II dynamics at the CCND1 locus.
  • This leads to increased CCND1 transcription and altered splicing, resulting in high levels of the oncogenic cyclin D1b splice isoform.
  • The cyclin D1b isoform promotes Ewing sarcoma cell growth.

Conclusions:

  • Dysregulation of transcriptional regulators in disease can directly cause aberrant mRNA splicing.
  • This mechanism, exemplified by EWS in Ewing sarcoma, highlights a critical interplay between transcription and splicing in cancer.
  • Understanding these connections may reveal new therapeutic targets for various cancers.

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