Snail and Slug promote epithelial-mesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3
Authors: Elizabeth D Hay
Bjorn R Olsen
Damian Medici
Journal: Molecular biology of the cell (2008)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Snail; Slug; beta-catenin; TCF-4; transcription complexes
Affiliations: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., *Department of Cell Biology, Harvard Medical School, Boston, MA 02115; and, Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115

Abstract:  Members of the Snail family of transcription factors have been shown to induce epithelial-mesenchymal transition (EMT), a fundamental mechanism of embryogenesis and progressive disease. Here, we show that Snail and Slug promote formation of beta-catenin-T-cell factor (TCF)-4 transcription complexes that bind to the promoter of the TGF-beta3 gene to increase its transcription. Subsequent transforming growth factor (TGF)-beta3 signaling increases LEF-1 gene expression causing formation of beta-catenin-lymphoid enhancer factor (LEF)-1 complexes that initiate EMT. TGF-beta1 or TGF-beta2 stimulates this signaling mechanism by up-regulating synthesis of Snail and Slug. TGF-beta1- and TGF-beta2-induced EMT were found to be TGF-beta3 dependent, establishing essential roles for multiple TGF-beta isoforms. Finally, we determined that beta-catenin-LEF-1 complexes can promote EMT without upstream signaling pathways. These findings provide evidence for a unified signaling mechanism driven by convergence of multiple TGF-beta and TCF signaling molecules that confers loss of cell-cell adhesion and acquisition of the mesenchymal phenotype. 

Retracted: No

PubPeer comments:
 Figure 3C. More similar than you would expect. ![file] , 
 Dear Sir Madam Ficus Caloplina: Thank you for your comment. The original picture of Figure 3C is shown below. When the paper was submitted to PNAS for publication, lane lane 5 of western blots for COX-2 and beta-Actin was removed to avoid duplication of sample (NS-398+Bystander). Additionally, some u201cfree spaceu201d between lanes 2 and 3 was organized. In retrospect, it was a bad idea of Dr. HN Zhou to simplify the original blot data, which now cause the avoidable confusion with the beta-Actin loading control. We appreciate your attention to details of our paper and hope that the explanation is satisfactory. ![file] , 
 Dear Sir Madam Ficus Caloplina, Thank you for your comment. The original picture of Figure 3C is shown below. Some modification was done before publication. Lane 5 of western blots for COX-2 and beta-Actin was removed to avoid duplication of the sample (NS-398+Bystander). Additionally, some u201cfree spaceu201d between lanes 2 and 3 was introduced. We think now that it was not a good idea that caused some confusion with beta-Actin images in the modified published Figure 3C, which could further induce a question about loading control. We appreciate your attention to the details of our paper and hope you are convinced by our explanation. ![file] **Original Figure 3C. **The expression of COX 2 protein in non-irradiated bystander cells determined by Western blotting. , 
 #2 I am still confused. Actin lanes 2 and 4 in the published figure 3C look very similar. Lane 4 Actin you posted has a vertical spike on top of its highest hump and a dark left end. I do not see these features in lane 4 in lane as published in figure 3C. , 
 We present here the comparison of actin lanes, which was performed by Ficus Caloplina, at a higher magnification, together with our original and published actin westerns. The actin lane 4 and mirrored lane 2 are indeed very similar, almost identical, with some difference in size in Fig.3C. In contrast, lanes 3 and 1 are not symmetrical. In our original actin blot with 5 lanes, there is a similarity between all actin lanes with the corresponding lanes in Fig.3C. However, lanes 2 and 4 demonstrate only restricted mirror symmetry. We think that the new actin western, which was performed in a parallel with published image, is a better reflection for loading control data. Thank you for the continuous interest in our publication. ,