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Invasive cells follow Snail's slow and persistent pace.

García de Herreros A, Moustakas A - Cell Cycle (2014)

View Article: PubMed Central - PubMed

Affiliation: a Cancer Research Program; Institut Hospital del Mar d'Investigacions Mèdiques and Departament de Ciències Experimentals i de la Salut; Universitat Pompeu Fabra; Barcelona, Spain.

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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... EMT is induced by several cytokines and growth factors being TGF-β that with a more general effect... The article by Thakur et al. in this issue of Cell Cycle has investigated the mechanism of activation of Snail1 transcription by TGF-β... 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... 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... 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... 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... It remains to be established how general this later response is because in other cells Snail1 activation by TGF-β is transient... Anyhow, the new model supports the idea that the molecular elements acting on EMT signaling pathways, such as p38α in this case, do not control a single but several steps... The authors also show that TGF-β decreases GSK3β activity by phosphorylating this enzyme on Ser9... Moreover, GSK3-β inhibition also enhances the stability and transcriptional function of β-catenin, an activity upregulated in migrating and invasive tumoral cells (Fig.  1)... Furthermore, since TGF-β regulates a cohort of pro-invasive and metastatic genes using the Smad and activating protein 1 (AP1, i.e., Jun-Fos family) transcriptional complexes, it will be of great interest to determine the impact of TRAF6/TAK1/Jun kinase pathway on the regulation of specific matrix metalloprotease genes.

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Figure 1. Schema of TGF-β-induced activation of Snail1 expression. Indirect functional actions are indicated by dashed lines. Protein kinases are shown as rectangles and transcription factors as ovals. Colored molecules indicate those most rigorously investigated in the present study. See text for details.
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Figure 1: Figure 1. Schema of TGF-β-induced activation of Snail1 expression. Indirect functional actions are indicated by dashed lines. Protein kinases are shown as rectangles and transcription factors as ovals. Colored molecules indicate those most rigorously investigated in the present study. See text for details.

Mentions: The authors also show that TGF-β decreases GSK3β activity by phosphorylating this enzyme on Ser9. It remains to be established if this phosphorylation is mediated by the protein kinase that normally acts on this substrate, Akt and if so, how activation of Akt is performed by TGF-β. GSK3β inactivation is crucial for EMT since it opposes to Snail1 activation acting at different levels: transcriptionally, preventing not only c-Jun but also NF-κB binding to Snai1 promoter; and (2) de-stabilizing Snail1 protein.1 Moreover, GSK3-β inhibition also enhances the stability and transcriptional function of β-catenin, an activity upregulated in migrating and invasive tumoral cells (Fig. 1).


Invasive cells follow Snail's slow and persistent pace.

García de Herreros A, Moustakas A - Cell Cycle (2014)

Figure 1. Schema of TGF-β-induced activation of Snail1 expression. Indirect functional actions are indicated by dashed lines. Protein kinases are shown as rectangles and transcription factors as ovals. Colored molecules indicate those most rigorously investigated in the present study. See text for details.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128875&req=5

Figure 1: Figure 1. Schema of TGF-β-induced activation of Snail1 expression. Indirect functional actions are indicated by dashed lines. Protein kinases are shown as rectangles and transcription factors as ovals. Colored molecules indicate those most rigorously investigated in the present study. See text for details.
Mentions: The authors also show that TGF-β decreases GSK3β activity by phosphorylating this enzyme on Ser9. It remains to be established if this phosphorylation is mediated by the protein kinase that normally acts on this substrate, Akt and if so, how activation of Akt is performed by TGF-β. GSK3β inactivation is crucial for EMT since it opposes to Snail1 activation acting at different levels: transcriptionally, preventing not only c-Jun but also NF-κB binding to Snai1 promoter; and (2) de-stabilizing Snail1 protein.1 Moreover, GSK3-β inhibition also enhances the stability and transcriptional function of β-catenin, an activity upregulated in migrating and invasive tumoral cells (Fig. 1).

View Article: PubMed Central - PubMed

Affiliation: a Cancer Research Program; Institut Hospital del Mar d'Investigacions Mèdiques and Departament de Ciències Experimentals i de la Salut; Universitat Pompeu Fabra; Barcelona, Spain.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

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... EMT is induced by several cytokines and growth factors being TGF-β that with a more general effect... The article by Thakur et al. in this issue of Cell Cycle has investigated the mechanism of activation of Snail1 transcription by TGF-β... 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... 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... 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... 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... It remains to be established how general this later response is because in other cells Snail1 activation by TGF-β is transient... Anyhow, the new model supports the idea that the molecular elements acting on EMT signaling pathways, such as p38α in this case, do not control a single but several steps... The authors also show that TGF-β decreases GSK3β activity by phosphorylating this enzyme on Ser9... Moreover, GSK3-β inhibition also enhances the stability and transcriptional function of β-catenin, an activity upregulated in migrating and invasive tumoral cells (Fig.  1)... Furthermore, since TGF-β regulates a cohort of pro-invasive and metastatic genes using the Smad and activating protein 1 (AP1, i.e., Jun-Fos family) transcriptional complexes, it will be of great interest to determine the impact of TRAF6/TAK1/Jun kinase pathway on the regulation of specific matrix metalloprotease genes.

Show MeSH