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CREB3L2-PPARgamma fusion mutation identifies a thyroid signaling pathway regulated by intramembrane proteolysis

Weng-Onn Lui1, Lingchun Zeng, Victoria Rehrmann

  • 1Department of Pathology, University of Chicago Medical Center, Chicago, Illinois 60637, USA.

Cancer Research
|September 2, 2008
PubMed

Insights

Scientists discovered a new CREB3L2-PPARgamma gene fusion in thyroid cancer, disrupting normal cell signaling. This finding advances understanding of thyroid carcinoma and potential targeted therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Gene fusions are key in identifying cancer pathways and developing targeted therapies.
  • Somatic gene fusions, including those involving PPARgamma, are implicated in various cancers.
  • Thyroid carcinoma research seeks to uncover novel mutations for improved diagnostics and treatments.

Purpose of the Study:

  • To report the discovery of a novel CREB3L2-PPARgamma gene fusion mutation in thyroid carcinoma.
  • To investigate the oncogenic mechanism of the CREB3L2-PPARgamma fusion protein.
  • To elucidate the role of CREB3L2 and its intramembrane proteolysis in thyroid cell signaling.

Main Methods:

  • Identification of the CREB3L2-PPARgamma fusion via cytogenetic analysis (t(3;7)(p25;q34)).
  • Characterization of the fusion protein's domains and oncogenic activity through engineered overexpression in human thyroid cells.
  • Analysis of wild-type CREB3L2 processing via intramembrane proteolysis and its transcriptional activity.
  • Assessment of CREB3L2-PPARgamma's impact on gene expression (EVX1, thyroglobulin) in thyroid cells.

Main Results:

  • A novel CREB3L2-PPARgamma fusion mutation was identified in a subset of thyroid follicular carcinomas.
  • The fusion protein, CREB3L2-PPARgamma, demonstrated dominant oncogenic activity, inducing significant cell proliferation.
  • Wild-type CREB3L2 undergoes regulated intramembrane proteolysis, yielding a nuclear form that regulates gene transcription.
  • CREB3L2-PPARgamma inhibited key thyroid-specific gene expression, including thyroglobulin, and altered EVX1 transcription.

Conclusions:

  • The CREB3L2-PPARgamma fusion represents a newly identified oncogenic driver in thyroid carcinoma.
  • Regulated intramembrane proteolysis of CREB3L2 is a critical thyroid signaling pathway disrupted by this fusion.
  • This discovery opens avenues for molecular diagnostics and targeted therapeutic strategies for thyroid cancer.

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