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

Nadine Hempel, Tam How, Simon J. Cooper, Tyler R. Green, Mei Dong, John A. Copland, Christopher G. Wood, Gerard C. Blobe

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The type III transforming growth factor-beta receptor (TβRIII or betaglycan) is a ubiquitously expressed transforming growth factor-beta (TGF-β) superfamily coreceptor with essential roles in embryonic development. Recent studies have defined a role for TβRIII in the pathogenesis of human cancers, with frequent loss of TβRIII expression at the message and protein level. Mechanisms for the loss of TβRIII expression remain to be fully defined. Advanced human cancers often have elevated circulating levels of TGF-β1. Here, we define a specific role for TGF-β1 in negatively regulating TβRIII at the message level in breast and ovarian cancer models. TGF-β1 decreased TβRIII message and protein levels in ovarian (Ovca420) and breast cancer (MDA-MB-231) cell lines in both a dose- and time-dependent manner. TGF-β1-mediated TβRIII repression is mediated by the type I TGF-β 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 TβRIII expression. Mechanistically, TGF-β1 does not affect TβRIII messenger RNA (mRNA) stability, but instead directly regulates the TβRIII 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-β1 and constitutively active ALK5. Taken together, these studies define TGF-β1-mediated downregulation of TβRIII mRNA expression through effects on the ALK5/Smad2/3 pathway on the TGFBR3 gene proximal promoter as a potential mechanism for decreased TβRIII expression in human cancers.

Original languageEnglish (US)
Pages (from-to)905-912
Number of pages8
JournalCarcinogenesis
Volume29
Issue number5
DOIs
StatePublished - May 1 2008

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Transforming Growth Factor beta
Ovarian Neoplasms
Breast Neoplasms
Neoplasms
Messenger RNA
betaglycan
RNA Stability
Genes
Embryonic Development
Proteins
Down-Regulation
TGF-beta type I receptor
Cell Line

ASJC Scopus subject areas

  • Cancer Research

Cite this

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-β receptor is negatively regulated by TGF-β. Carcinogenesis, 29(5), 905-912. https://doi.org/10.1093/carcin/bgn049

Expression of the type III TGF-β receptor is negatively regulated by TGF-β. / Hempel, Nadine; How, Tam; Cooper, Simon J.; Green, Tyler R.; Dong, Mei; Copland, John A.; Wood, Christopher G.; Blobe, Gerard C.

In: Carcinogenesis, Vol. 29, No. 5, 01.05.2008, p. 905-912.

Research output: Contribution to journalArticle

Hempel, N, How, T, Cooper, SJ, Green, TR, Dong, M, Copland, JA, Wood, CG & Blobe, GC 2008, 'Expression of the type III TGF-β receptor is negatively regulated by TGF-β', Carcinogenesis, vol. 29, no. 5, pp. 905-912. 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-β receptor is negatively regulated by TGF-β. Carcinogenesis. 2008 May 1;29(5):905-912. https://doi.org/10.1093/carcin/bgn049
Hempel, Nadine ; How, Tam ; Cooper, Simon J. ; Green, Tyler R. ; Dong, Mei ; Copland, John A. ; Wood, Christopher G. ; Blobe, Gerard C. / Expression of the type III TGF-β receptor is negatively regulated by TGF-β. In: Carcinogenesis. 2008 ; Vol. 29, No. 5. pp. 905-912.
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