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The T-box transcription factor TBX3 provides an important link between embryonic development and cancer. TBX3 mediates limb, mammary gland and heart development and, in humans, mutations resulting in haplo-insufficiency of TBX3 lead to ulnar-mammary syndrome. Importantly, the de-regulation of TBX3 gene expression has been linked to several cancers, where it acts to suppress senescence and promotes proliferation and tumour invasion. Despite the negative impact of de-regulated TBX3 expression as seen by developmental defects and cancer, surprisingly little is known about the regulation of the TBX3 gene. In the present paper, we show that the phorbol ester PMA increases TBX3 protein and mRNA levels in a protein kinase C-dependent manner via the AP-1 (activator protein 1) transcription factors c-Jun and JunB. Furthermore, these AP-1 factors are shown to mediate the activation of the TBX3 gene by binding a non-consensus PMA-response element in the TBX3 promoter in vitro and in vivo. We also demonstrate that TBX3 contributes to the PMA-induced migration previously observed for the MCF-7 breast epithelium cancer cell line. Our present results reveal a previously unidentified pathway that up-regulates TBX3 expression and provides additional evidence that increased levels of TBX3 contribute to metastasis.

Original publication

DOI

10.1042/BJ20100886

Type

Journal article

Journal

Biochem J

Publication Date

01/01/2011

Volume

433

Pages

145 - 153

Keywords

Breast Neoplasms, Cell Movement, Female, Gene Expression Regulation, Neoplastic, Humans, Neoplasm Metastasis, RNA, Messenger, Response Elements, T-Box Domain Proteins, Tetradecanoylphorbol Acetate, Transcription Factor AP-1, Up-Regulation