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TGF beta-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail1
Uppsala Univ, Sci Life Lab, Ludwig Inst Canc Res, Uppsala, Sweden.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Uppsala Univ, Sci Life Lab, Ludwig Inst Canc Res, Uppsala, Sweden.
Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, Uppsala, Sweden.
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2014 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 13, no 15, 2400-2414 p.Article in journal (Refereed) Published
Abstract [en]

High levels of transforming growth factor-beta (TGF beta) correlate with poor prognosis for patients with prostate cancer and other cancers. TGF beta 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. TGF beta conveys its signals upon binding to type I and type II serine/threonine kinase receptors (T beta RI/II); phosphorylation of Smad2 and Smad3 promotes their association with Smad4, which regulates expression of targets genes, such as Smad7, p21, and c-Jun. TGF beta also activates the ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6), which associates with T beta RI and activates the p38 mitogen-activated protein kinase (MAPK) pathway. Snail1 is a key transcription factor, induced by TGF beta 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 TGF beta-TRAF6-p38 MAPK pathway promotes both c-Jun expression and its activation via p38a-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) 3 beta 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.

Place, publisher, year, edition, pages
2014. Vol. 13, no 15, 2400-2414 p.
Keyword [en]
c-Jun, invasion, p38 MAPK, prostate cancer, Smads, Snail1, TGF beta, TRAF6
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:umu:diva-93495DOI: 10.4161/cc.29339ISI: 000340720900016OAI: oai:DiVA.org:umu-93495DiVA: diva2:761878
Available from: 2014-11-09 Created: 2014-09-23 Last updated: 2017-12-05Bibliographically approved

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Gudey, Shyam KumarBergh, AndersLandström, Marene
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