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TGFβ-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail1.

Thakur N, Gudey SK, Marcusson A, Fu JY, Bergh A, Heldin CH, Landström M - Cell Cycle (2014)

Bottom Line: In this study, we have identified a novel binding site for c-Jun in the promoter of the Snail1 gene and report that the activation of the TGFβ-TRAF6-p38 MAPK pathway promotes both c-Jun expression and its activation via p38α-dependent phosphorylation of c-Jun at Ser63.The TRAF6-dependent activation of p38 also leads to increased stability of c-Jun, due to p38-dependent inactivation of glycogen synthase kinase (GSK) 3β by phosphorylation at Ser9.Thus, our findings elucidate a novel role for the p38 MAPK pathway in stimulated cells, leading to activation of c-Jun and its binding to the promoter of Snail1, thereby triggering motility and invasiveness of aggressive human prostate cancer cells.

View Article: PubMed Central - PubMed

Affiliation: a Ludwig Institute for Cancer Research; Science for Life Laboratory; Uppsala University; Uppsala, Sweden.

ABSTRACT
High levels of transforming growth factor-β (TGFβ) correlate with poor prognosis for patients with prostate cancer and other cancers. TGFβ is a multifunctional cytokine and crucial regulator of cell fate, such as epithelial to mesenchymal transition (EMT), which is implicated in cancer invasion and progression. TGFβ conveys its signals upon binding to type I and type II serine/threonine kinase receptors (TβRI/II); phosphorylation of Smad2 and Smad3 promotes their association with Smad4, which regulates expression of targets genes, such as Smad7, p21, and c-Jun. TGFβ also activates the ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6), which associates with TβRI and activates the p38 mitogen-activated protein kinase (MAPK) pathway. Snail1 is a key transcription factor, induced by TGFβ that promotes migration and invasion of cancer cells. In this study, we have identified a novel binding site for c-Jun in the promoter of the Snail1 gene and report that the activation of the TGFβ-TRAF6-p38 MAPK pathway promotes both c-Jun expression and its activation via p38α-dependent phosphorylation of c-Jun at Ser63. The TRAF6-dependent activation of p38 also leads to increased stability of c-Jun, due to p38-dependent inactivation of glycogen synthase kinase (GSK) 3β by phosphorylation at Ser9. Thus, our findings elucidate a novel role for the p38 MAPK pathway in stimulated cells, leading to activation of c-Jun and its binding to the promoter of Snail1, thereby triggering motility and invasiveness of aggressive human prostate cancer cells.

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Figure 6. c-Jun is required for TGFβ-induced p21 expression. Cell lysates derived from PC-3U cells transiently transfected with si-CTRL or si-c-Jun, and treated or not with TGFβ for the indicated time periods, were subjected to immunoblotting with antiserum that recognize p21, p-Ser63-c-Jun, total c-Jun and actin. Data from non-treated (NT) PC-3U cells are also shown.
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Figure 6: Figure 6. c-Jun is required for TGFβ-induced p21 expression. Cell lysates derived from PC-3U cells transiently transfected with si-CTRL or si-c-Jun, and treated or not with TGFβ for the indicated time periods, were subjected to immunoblotting with antiserum that recognize p21, p-Ser63-c-Jun, total c-Jun and actin. Data from non-treated (NT) PC-3U cells are also shown.

Mentions: To investigate the effect of c-Jun on its own expression, a dominant negative c-Jun plasmid (Flag-tagged DN c-Jun; lacking 168 amino-acid residues in its N-terminal part, containing the transactivation domain) was transfected into PC-3U cells. The expression of p21 and c-Jun was inhibited by DN c-Jun supporting the notion that c-Jun regulates its own expression (Fig. 5A), as expected.40 In PC-3U cells transfected with DN c-Jun, the mRNA expression of PAI1, a target gene of TGFβ, was slightly decreased in DN c-Jun transfected cells (Fig. 5B), while expression of p21 and c-Jun mRNA was inhibited (Fig. 5C and D). Moreover, knock-down of c-Jun by siRNA, led to inhibition of TGFβ-induced expression of p21, further illustrating that c-Jun is required for the expression of p21 (Fig. 6). From these data, we conclude that c-Jun contributes to the TGFβ-induced regulation of p21 expression.


TGFβ-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail1.

Thakur N, Gudey SK, Marcusson A, Fu JY, Bergh A, Heldin CH, Landström M - Cell Cycle (2014)

Figure 6. c-Jun is required for TGFβ-induced p21 expression. Cell lysates derived from PC-3U cells transiently transfected with si-CTRL or si-c-Jun, and treated or not with TGFβ for the indicated time periods, were subjected to immunoblotting with antiserum that recognize p21, p-Ser63-c-Jun, total c-Jun and actin. Data from non-treated (NT) PC-3U cells are also shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 6: Figure 6. c-Jun is required for TGFβ-induced p21 expression. Cell lysates derived from PC-3U cells transiently transfected with si-CTRL or si-c-Jun, and treated or not with TGFβ for the indicated time periods, were subjected to immunoblotting with antiserum that recognize p21, p-Ser63-c-Jun, total c-Jun and actin. Data from non-treated (NT) PC-3U cells are also shown.
Mentions: To investigate the effect of c-Jun on its own expression, a dominant negative c-Jun plasmid (Flag-tagged DN c-Jun; lacking 168 amino-acid residues in its N-terminal part, containing the transactivation domain) was transfected into PC-3U cells. The expression of p21 and c-Jun was inhibited by DN c-Jun supporting the notion that c-Jun regulates its own expression (Fig. 5A), as expected.40 In PC-3U cells transfected with DN c-Jun, the mRNA expression of PAI1, a target gene of TGFβ, was slightly decreased in DN c-Jun transfected cells (Fig. 5B), while expression of p21 and c-Jun mRNA was inhibited (Fig. 5C and D). Moreover, knock-down of c-Jun by siRNA, led to inhibition of TGFβ-induced expression of p21, further illustrating that c-Jun is required for the expression of p21 (Fig. 6). From these data, we conclude that c-Jun contributes to the TGFβ-induced regulation of p21 expression.

Bottom Line: In this study, we have identified a novel binding site for c-Jun in the promoter of the Snail1 gene and report that the activation of the TGFβ-TRAF6-p38 MAPK pathway promotes both c-Jun expression and its activation via p38α-dependent phosphorylation of c-Jun at Ser63.The TRAF6-dependent activation of p38 also leads to increased stability of c-Jun, due to p38-dependent inactivation of glycogen synthase kinase (GSK) 3β by phosphorylation at Ser9.Thus, our findings elucidate a novel role for the p38 MAPK pathway in stimulated cells, leading to activation of c-Jun and its binding to the promoter of Snail1, thereby triggering motility and invasiveness of aggressive human prostate cancer cells.

View Article: PubMed Central - PubMed

Affiliation: a Ludwig Institute for Cancer Research; Science for Life Laboratory; Uppsala University; Uppsala, Sweden.

ABSTRACT
High levels of transforming growth factor-β (TGFβ) correlate with poor prognosis for patients with prostate cancer and other cancers. TGFβ is a multifunctional cytokine and crucial regulator of cell fate, such as epithelial to mesenchymal transition (EMT), which is implicated in cancer invasion and progression. TGFβ conveys its signals upon binding to type I and type II serine/threonine kinase receptors (TβRI/II); phosphorylation of Smad2 and Smad3 promotes their association with Smad4, which regulates expression of targets genes, such as Smad7, p21, and c-Jun. TGFβ also activates the ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6), which associates with TβRI and activates the p38 mitogen-activated protein kinase (MAPK) pathway. Snail1 is a key transcription factor, induced by TGFβ that promotes migration and invasion of cancer cells. In this study, we have identified a novel binding site for c-Jun in the promoter of the Snail1 gene and report that the activation of the TGFβ-TRAF6-p38 MAPK pathway promotes both c-Jun expression and its activation via p38α-dependent phosphorylation of c-Jun at Ser63. The TRAF6-dependent activation of p38 also leads to increased stability of c-Jun, due to p38-dependent inactivation of glycogen synthase kinase (GSK) 3β by phosphorylation at Ser9. Thus, our findings elucidate a novel role for the p38 MAPK pathway in stimulated cells, leading to activation of c-Jun and its binding to the promoter of Snail1, thereby triggering motility and invasiveness of aggressive human prostate cancer cells.

Show MeSH
Related in: MedlinePlus