Carcinogenesis Advance Access published online on February 24, 2008
Carcinogenesis, doi:10.1093/carcin/bgn049
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Expression of the Type III TGF-β Receptor is negatively regulated by TGF-β
Department of Medicine
1 Department of Medicine and Pharmacology, Duke University Medical Center Durham, NC 27710
2 Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic College of Medicine, Jacksonville, Jacksonville, FL 32224
3 Department of Urology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
4 Department of Medicine and Cancer Biology, Duke University Medical Center Durham, NC 27710
Corresponding author: Gerard C. Blobe, 354 LSRC, Research Drive, Box 91004, Duke University Medical Center, Durham NC 27708, tel: (919) 668-1352, fax: (919) 681-6906, Email: blobe001{at}mc.duke.edu
The type III TGF-ß Receptor (TßRIII, or betaglycan) is a ubiquitously expressed TGF-ß superfamily co-receptor, with essential roles in embryonic development. Recent studies have defined a role for TßRIII in the pathogenesis of human cancers, with frequent loss of TßRIII expression at the message and protein level. Mechanisms for loss of TßRIII expression remain to be fully defined. Advanced human cancers often have elevated circulating levels of TGF-ß1. Here we define a specific role for TGF-ß1 in negatively regulating TßRIII at the message level in breast and ovarian cancer models. TGF-ß1 decreased TßRIII message and protein levels in ovarian (Ovca420) and breast cancer (MDA-MB-231) cell lines in both a dose and time-dependent manner. TGF-ß1-mediated TßRIII repression is mediated by the ALK5/Smad2/3 pathway as the ALK5 inhibitor, SB431542, abrogated this effect, while expression of constitutively active ALK5 was sufficient to repress TßRIII expression. Mechanistically, TGF-ß1 does not affect TßRIII mRNA stability, but instead directly regulates the TßRIII 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-ß1 and constitutively active ALK5. Taken together, these studies define TGF-ß1-mediated downregulation of TßRIII mRNA expression through effects on the ALK5/Smad2/3 pathway on the TßRIII gene proximal promoter as a potential mechanism for decreased TßRIII expression in human cancers.
Key Words: Type III TGF-β Receptor • betaglycan • co-receptor • TGF-β • transcriptional regulation
* These authors contributed equally.
Current Address NH: Department of Immunology and Microbial Diseases, Albany Medical College, Albany, NY12208
Received November 5, 2007; revised January 22, 2008; accepted February 9, 2008.
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