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Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta

Nadine Hempel1, Tam How, Simon J Cooper

  • 1Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Carcinogenesis
|February 27, 2008
PubMed

Insights

Transforming growth factor-beta 1 (TGF-beta1) downregulates the TGF-beta III receptor (TbetaRIII) in cancer cells. This occurs via the ALK5/Smad2/3 pathway affecting the TGFBR3 gene promoter, explaining TbetaRIII loss in cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Type III transforming growth factor-beta receptor (TbetaRIII) is crucial for embryonic development.
  • Loss of TbetaRIII expression is observed in human cancers, but mechanisms are unclear.
  • Elevated circulating TGF-beta1 is common in advanced cancers.

Purpose of the Study:

  • To investigate the role of TGF-beta1 in regulating TbetaRIII expression in cancer.
  • To elucidate the molecular mechanisms underlying TGF-beta1-mediated TbetaRIII downregulation.

Main Methods:

  • Utilized breast and ovarian cancer cell lines (MDA-MB-231, Ovca420).
  • Assessed TbetaRIII message and protein levels following TGF-beta1 treatment.
  • Employed ALK5 inhibitor (SB431542) and constitutively active ALK5.
  • Analyzed TGFBR3 gene promoter activity and mRNA stability.

Main Results:

  • TGF-beta1 dose- and time-dependently decreased TbetaRIII mRNA and protein levels.
  • The ALK5/Smad2/3 pathway mediates TGF-beta1's repressive effect on TbetaRIII.
  • TGF-beta1 regulates the proximal promoter of the TGFBR3 gene, not mRNA stability.
  • Constitutively active ALK5 repressed TbetaRIII expression.

Conclusions:

  • TGF-beta1 downregulates TbetaRIII expression via the ALK5/Smad2/3 pathway.
  • Regulation occurs at the level of the TGFBR3 gene proximal promoter.
  • This mechanism contributes to decreased TbetaRIII expression in human cancers.

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