FIGURE 6.

Scheme of the different regulation levels of Zeb1 expression by Snail1 and TGF-β. Up-regulation of Snail1 by TGF-β increases Zeb1 protein acting on different levels: 1) it decreases the expression of miRNA200 that destabilizes Zeb1 RNA; 2) it stimulates Zeb1 protein stability through the inhibition of the function of the still unidentified ubiquitin ligase involved in Zeb1 degradation; and 3) it activates Zeb1 gene transcription. This stimulation is mediated by the activation of two transcriptional factors, Twist and Ets1 that bind to different elements on the Zeb1 promoter. Snail1 also up-regulates Zeb1 transcription at several levels, because it promotes Ets1 translocation to the nucleus, increases Twist protein stability, and is required for the stimulation in Twist1 RNA caused by TGF-β. In addition, full Snail1 up-regulation by TGFβ also requires Twist expression (depicted by a dotted line).