Skip to main content
Journal cover image

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

Publication ,  Journal Article
Hempel, N; How, T; Cooper, SJ; Green, TR; Dong, M; Copland, JA; Wood, CG; Blobe, GC
Published in: Carcinogenesis
May 2008

The type III transforming growth factor-beta receptor (TbetaRIII or betaglycan) is a ubiquitously expressed transforming growth factor-beta (TGF-beta) superfamily coreceptor with essential roles in embryonic development. Recent studies have defined a role for TbetaRIII in the pathogenesis of human cancers, with frequent loss of TbetaRIII expression at the message and protein level. Mechanisms for the loss of TbetaRIII expression remain to be fully defined. Advanced human cancers often have elevated circulating levels of TGF-beta1. Here, we define a specific role for TGF-beta1 in negatively regulating TbetaRIII at the message level in breast and ovarian cancer models. TGF-beta1 decreased TbetaRIII message and protein levels in ovarian (Ovca420) and breast cancer (MDA-MB-231) cell lines in both a dose- and time-dependent manner. TGF-beta1-mediated TbetaRIII repression is mediated by the type I TGF-beta receptor/Smad2/3 pathway as the activin receptor-like kinase 5 (ALK5) inhibitor, SB431542, abrogated this effect, while the expression of constitutively active ALK5 was sufficient to repress TbetaRIII expression. Mechanistically, TGF-beta1 does not affect TbetaRIII messenger RNA (mRNA) stability, but instead directly regulates the TbetaRIII promoter. We define alternative promoters for the TGFBR3 gene, a distal and proximal promoter. Although both promoters are active, only the proximal promoter was responsive and negatively regulated by TGF-beta1 and constitutively active ALK5. Taken together, these studies define TGF-beta1-mediated downregulation of TbetaRIII mRNA expression through effects on the ALK5/Smad2/3 pathway on the TGFBR3 gene proximal promoter as a potential mechanism for decreased TbetaRIII expression in human cancers.

Duke Scholars

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

May 2008

Volume

29

Issue

5

Start / End Page

905 / 912

Location

England

Related Subject Headings

  • Transforming Growth Factor beta1
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, Transforming Growth Factor beta
  • RNA, Neoplasm
  • RNA, Messenger
  • Proteoglycans
  • Protein Kinase Inhibitors
  • Promoter Regions, Genetic
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Hempel, N., How, T., Cooper, S. J., Green, T. R., Dong, M., Copland, J. A., … Blobe, G. C. (2008). Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta. Carcinogenesis, 29(5), 905–912. https://doi.org/10.1093/carcin/bgn049
Hempel, Nadine, Tam How, Simon J. Cooper, Tyler R. Green, Mei Dong, John A. Copland, Christopher G. Wood, and Gerard C. Blobe. “Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta.Carcinogenesis 29, no. 5 (May 2008): 905–12. https://doi.org/10.1093/carcin/bgn049.
Hempel N, How T, Cooper SJ, Green TR, Dong M, Copland JA, et al. Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta. Carcinogenesis. 2008 May;29(5):905–12.
Hempel, Nadine, et al. “Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta.Carcinogenesis, vol. 29, no. 5, May 2008, pp. 905–12. Pubmed, doi:10.1093/carcin/bgn049.
Hempel N, How T, Cooper SJ, Green TR, Dong M, Copland JA, Wood CG, Blobe GC. Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta. Carcinogenesis. 2008 May;29(5):905–912.
Journal cover image

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

May 2008

Volume

29

Issue

5

Start / End Page

905 / 912

Location

England

Related Subject Headings

  • Transforming Growth Factor beta1
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, Transforming Growth Factor beta
  • RNA, Neoplasm
  • RNA, Messenger
  • Proteoglycans
  • Protein Kinase Inhibitors
  • Promoter Regions, Genetic
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis