| First Author | Miranda MZ | Year | 2017 |
| Journal | J Biol Chem | Volume | 292 |
| Issue | 36 | Pages | 14902-14920 |
| PubMed ID | 28739802 | Mgi Jnum | J:246264 |
| Mgi Id | MGI:5917177 | Doi | 10.1074/jbc.M117.780502 |
| Citation | Miranda MZ, et al. (2017) TGF-beta1 regulates the expression and transcriptional activity of TAZ protein via a Smad3-independent, myocardin-related transcription factor-mediated mechanism. J Biol Chem 292(36):14902-14920 |
| abstractText | Hippo pathway transcriptional coactivators TAZ and YAP and the TGF-beta1 (TGFbeta) effector Smad3 regulate a common set of genes, can physically interact, and exhibit multilevel cross-talk regulating cell fate-determining and fibrogenic pathways. However, a key aspect of this cross-talk, TGFbeta-mediated regulation of TAZ or YAP expression, remains uncharacterized. Here, we show that TGFbeta induces robust TAZ but not YAP protein expression in both mesenchymal and epithelial cells. TAZ levels, and to a lesser extent YAP levels, also increased during experimental kidney fibrosis. Pharmacological or genetic inhibition of Smad3 did not prevent the TGFbeta-induced TAZ up-regulation, indicating that this canonical pathway is dispensable. In contrast, inhibition of p38 MAPK, its downstream effector MK2 (e.g. by the clinically approved antifibrotic pirferidone), or Akt suppressed the TGFbeta-induced TAZ expression. Moreover, TGFbeta elevated TAZ mRNA in a p38-dependent manner. Myocardin-related transcription factor (MRTF) was a central mediator of this effect, as MRTF silencing/inhibition abolished the TGFbeta-induced TAZ expression. MRTF overexpression drove the TAZ promoter in a CC(A/T-rich)6GG (CArG) box-dependent manner and induced TAZ protein expression. TGFbeta did not act by promoting nuclear MRTF translocation; instead, it triggered p38- and MK2-mediated, Nox4-promoted MRTF phosphorylation and activation. Functionally, higher TAZ levels increased TAZ/TEAD-dependent transcription and primed cells for enhanced TAZ activity upon a second stimulus (i.e. sphingosine 1-phosphate) that induced nuclear TAZ translocation. In conclusion, our results uncover an important aspect of the cross-talk between TGFbeta and Hippo signaling, showing that TGFbeta induces TAZ via a Smad3-independent, p38- and MRTF-mediated and yet MRTF translocation-independent mechanism. |
