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Identification of cyclic adenosine 3',5'-monophosphate response element modulator as an activator of the human

Mike S Fenton1, Kenneth M Marion, Jerome M Hershman

  • 1Endocrinology Division, Veterans Affairs Greater Los Angeles Healthcare System and Department of Medicine, University of California Los Angeles School of Medicine, Los Angeles, California 90073, USA. fenton@ucla.edu

Endocrinology
|January 19, 2008
PubMed

Insights

Low Na(+)/I(-) symporter (NIS) gene expression hinders thyroid cancer treatment. Researchers found the cAMP response element modulator (CREM) activator is crucial for NIS gene expression, identifying it as a key factor in thyroid cancer therapy efficacy.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Oncology

Background:

  • Na(+)/I(-) symporter (NIS) gene expression is critical for radioactive iodide therapy efficacy in thyroid cancer.
  • Reduced NIS expression in some thyroid cancers limits treatment outcomes, with underlying molecular mechanisms poorly understood.
  • NIS gene transcription is regulated by thyroid-stimulating hormone-mediated cAMP/protein kinase A signaling via a NIS upstream enhancer (NUE).

Purpose of the Study:

  • To elucidate the molecular mechanisms governing NIS gene transcriptional activation in normal and thyroid cancer cells.
  • To identify novel factors involved in the regulation of NIS gene expression and NUE activity.
  • To investigate the role of cAMP response element modulator (CREM) activator in NIS expression.

Main Methods:

  • Comparative analysis of NIS gene expression and transcription complex components in normal thyroid cells and distinct thyroid cancer cell lines (BRAF-mutated and RET/PTC-rearranged).
  • Stimulation of cAMP pathway using forskolin to assess its effect on NIS gene expression and transcription factors.
  • Ectopic expression of CREM activator to determine its impact on NUE activity.

Main Results:

  • The cAMP response element modulator (CREM) activator was identified as a novel component essential for NIS gene expression.
  • The CREM complex was present in normal thyroid cells and BRAF-mutated cancer cells but absent in RET/PTC-rearranged cancer cells.
  • Absence of CREM in RET/PTC-rearranged cells correlated with reduced NUE activity and NIS expression; ectopic CREM expression restored NUE activity.

Conclusions:

  • CREM activator is a critical regulator of NIS gene expression and NUE activity.
  • Loss of CREM complex contributes to diminished NIS expression and NUE activity in certain thyroid cancers.
  • Targeting CREM may offer a therapeutic strategy to enhance NIS expression and improve radioactive iodide therapy for thyroid cancer patients.

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