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Transcriptional regulation of connexin 43 expression by retinoids and carotenoids: similarities and differences

Alex L Vine1, Yee M Leung, John S Bertram

  • 1Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii 96813, USA.

Molecular Carcinogenesis
|March 9, 2005
PubMed

Insights

Cancer-preventive retinoids and carotenoids upregulate connexin 43 (Cx43) expression, crucial for gap junctional communication (GJC). This study reveals direct transcriptional activation via a Sp1/Sp3 GC-box, independent of protein synthesis.

Area of Science:

  • Molecular biology
  • Cell biology
  • Cancer research

Background:

  • Gap junctions, formed by connexins, coordinate cell responses and are often deficient in tumors.
  • Restoring gap junctional communication (GJC) can reduce neoplastic growth.
  • Connexin 43 (Cx43) expression is upregulated by cancer-preventive retinoids and carotenoids, but the mechanism is unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which retinoids and carotenoids upregulate Cx43 expression.
  • To differentiate the gene activation pathways of retinoids versus non-pro-vitamin A carotenoids.
  • To identify the specific DNA elements and transcription factors involved in Cx43 gene regulation.

Main Methods:

  • Utilized Cx43 luciferase reporter constructs in F9 cells.
  • Employed retinoic acid receptor antagonist Ro 41-5253 to distinguish activation pathways.
  • Performed electrophoretic mobility shift assays (EMSA) to identify transcription factor binding.
  • Used site-directed mutagenesis to assess the role of the GC-box element.

Main Results:

  • Retinoids and non-pro-vitamin A carotenoids (astaxanthin, lycopene) activate Cx43 gene expression through distinct mechanisms.
  • Activation occurs via direct transcriptional regulation, not requiring new protein synthesis or affecting Cx43 mRNA half-life.
  • A critical responsive region (-158 bp to +209 bp) contains a Sp1/Sp3 GC-box, essential for retinoid induction.
  • Mutagenesis of the GC-box abolished retinoid responsiveness and increased basal transcription.

Conclusions:

  • Cx43 gene expression is directly transcriptionally activated by retinoids through a Sp1/Sp3 GC-box.
  • Retinoids and non-pro-vitamin A carotenoids employ separate molecular mechanisms for Cx43 gene induction.
  • Understanding these mechanisms may offer new strategies for cancer prevention and therapy by restoring GJC.

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