Requirement of TCF7L2 for TGF-beta-dependent transcriptional activation of the TMEPAI gene.

ABSTRACT: The TGF-? and Wnt pathways are involved in cell fate and tumorigenicity. A recent report indicated that a TGF-? target gene, TMEPAI (transmembrane prostate androgen-induced RNA), is possibly also a downstream target of Wnt signaling. Although TMEPAI was believed to be involved in tumorigenicity because of its blockage of TGF-? signaling, how TGF-? and Wnt signals affect the activation of the TMEPAI gene is not well understood. Herein, we show that the TMEPAI promoter is regulated synergistically by TGF-?/Smad and Wnt/?-catenin/T cell factor (TCF) 7L2. The critical cis-element for dual signals, termed TGF-?-responsive TCF7L2-binding element (TTE), is located in intron 1 of the TMEPAI gene. TCF7L2, but not Smad proteins, bound to TTE, whereas the disruption of TTE by mutagenesis remarkably counteracted both TGF-? and TCF7L2 responses. The introduction of mutations in critical Smad-binding elements blocked the activation of the TMEPAI promoter by TCF7L2. Furthermore, our DNA-protein interaction experiments revealed the indirect binding of TCF7L2 to Smad-binding elements via Smad3 upon TGF-? stimulation as well as its TGF-?-dependent association with TTE. We demonstrate that the Wnt/?-catenin/TCF7L2 pathway is preferentially able to alter the transcriptional regulation of the TGF-?-target gene, TMEPAI.

SUBMITTER: Nakano N 

PROVIDER: S-EPMC2992236 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature