The oncogenic TBX3 is a downstream target and mediator of the TGF-β1 signaling pathway

Mol Biol Cell. 2013 Nov;24(22):3569-76. doi: 10.1091/mbc.E13-05-0273. Epub 2013 Sep 11.

Abstract

The T-box transcription factor, TBX3, plays an important role in embryonic development, and haploinsufficiency of TBX3 causes ulnar-mammary syndrome. Overexpression of TBX3, on the other hand, is associated with several cancers, and preliminary evidence suggests that increased levels of TBX3 may inhibit cell proliferation but promote tumor migration and invasion. Although this suggests that deregulated levels of TBX3 are deleterious in development and promotes disease, very little is known about the signaling pathways that regulate TBX3 expression. Here we show that overexpressing TBX3 inhibits proliferative ability while promoting the migration of breast epithelial cells. We demonstrate that the transforming growth factor β1 (TGF-β1) pathway up-regulates TBX3 protein and mRNA levels and show a detailed transcriptional mechanism by which this occurs. Using in vitro and in vivo assays, we show that Smad3/4 and JunB bind and cooperatively regulate TBX3 promoter activity through a Smad-binding element at -67 base pairs. Further, we show that TBX3 plays a pivotal role in mediating the antiproliferative and promigratory role of TGF-β1 in breast epithelial and skin keratinocytes. This study identifies the TGF-β1 signaling pathway as a potentially important player in the regulation of TBX3 in development and cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Female
  • Gene Expression Regulation
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism*
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / drug effects
  • Mammary Glands, Human / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction*
  • Skin / cytology
  • Skin / drug effects
  • Skin / metabolism
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transforming Growth Factor beta1 / metabolism*
  • Transforming Growth Factor beta1 / pharmacology

Substances

  • JunB protein, human
  • RNA, Messenger
  • SMAD3 protein, human
  • SMAD4 protein, human
  • Smad3 Protein
  • Smad4 Protein
  • T-Box Domain Proteins
  • TBX3 protein, human
  • Transcription Factors
  • Transforming Growth Factor beta1