Invasive cells follow Snail’s slow and persistent pace

The term epithelial to mesenchymal transition (eMT) designs the conversion of an epithelial cell in another cell with a fibro-blastic-like shape. Besides being essential for embryo morphogenesis, eMT also provides tumoral cells with higher invasion and greater resistance to apoptosis and is related to the initial stages of tumor metastasis. Among the many mesenchymal genes induced during eMT, snail1 has received a great attention since it is rapidly upregulated at the onset of the process and is required for its completion. 1 eMT is induced by several cytokines and growth factors being TGF-β that with a more general effect. Actually, snail1 is rapidly induced by TGF-β not only in epithelial but also in mesenchymal cells and is required for a full response to this cytokine including the activation of invasion-related genes. 2 The article by Thakur et al. 3 in this issue of Cell Cycle has investigated the mechanism of activation of snail1 transcription by TGF-β. The TGF-β pathway includes smad proteins that get activated by the TGF-β receptor and accumulate on chromatin to regulate gene expression. 4 in parallel, TGF-β receptors activate various protein kinases by recruiting directly adaptor proteins such as shc and ubiquitin ligases such as TRAF6. Among these protein kinases, TGF-β activates TAK1 and the downstream effector p38 MAPK, at focus in the paper by Thakur et al. 3 This pathway is now shown to contribute via specific mechanisms to multiple physiological outcomes of TGF-β biology. specifically, the TRAF6/TAK1 module provides transcriptional inputs to various gene targets, such as snail1, that triggers cell invasion, and the cyclin-dependent kinase inhibitor p21 that feeds the cytostatic program and other pro-apoptotic genes. 3 interestingly, the TGF-β/TRAF6/TAK1 pathway shows selectivity and Thakur et al. report on genes (e.g., smad7) whose expression is not affected by this signaling module. The key open question in the TGF-β field has been the identification of transcription factors providing gene specificity. in this report the authors identify c-Jun as a TGF-β-dependent direct transcriptional activator of Snai1 gene. These results have several implications and open new lines of future research. For instance, the dual role of TGF-β on c-Jun, first inducing its phosphorylation on ser63 and its rapid activation and later its upregulation, might influence snail1 expression in a two-wave fashion: first promoting an acute response required for triggering the eMT, and later a more sustained one, involved in reinforcing the phenotype and associated to a …