Akt2 interacts with Snail1 in the E-cadherin promoter

Villagrasa, Patricia; Dı́az, Vı́ctor M.; Viñas-Castells, Rosa; Peiró, Sandra; Valle-Pérez, Beatriz Del; Dave, Natàlia; Rodríguez-Asiain, Arantza; Casal, J. Ignacio; Lizcano, José M.; Duñach, Mireia; Herreros, Antonio Garcı́a de

doi:10.1038/onc.2011.562

Cited by 28 publications

(28 citation statements)

References 47 publications

(79 reference statements)

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“…90 The pro-metastatic properties of Akt2 may reside in its capacity to regulate the activity of Twist1 and Snail1, 2 classical EMT-TFs. 91,92 Expression of both Twist1 and Akt2 was found to be elevated in highly invasive breast cancer cells, 91 and silencing of Akt2 decreased Twist1-induced migration and invasion. Moreover, Twist1 was found to bind E-box elements in the Akt2 promoter and thereby enhance its expression.…”

Section: Smad and Non-smad Signaling In Emtmentioning

confidence: 99%

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Reprogramming during epithelial to mesenchymal transition under the control of TGFβ

Tan¹,

Olsson

Moustakas

2014

Cell Adhesion & Migration

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Epithelial-mesenchymal transition (EMT) refers to plastic changes in epithelial tissue architecture. Breast cancer stromal cells provide secreted molecules, such as transforming growth factor b (TGFb), that promote EMT on tumor cells to facilitate breast cancer cell invasion, stemness and metastasis. TGFb signaling is considered to be abnormal in the context of cancer development; however, TGFb acting on breast cancer EMT resembles physiological signaling during embryonic development, when EMT generates or patterns new tissues. Interestingly, while EMT promotes metastatic fate, successful metastatic colonization seems to require the inverse process of mesenchymal-epithelial transition (MET). EMT and MET are interconnected in a timedependent and tissue context-dependent manner and are coordinated by TGFb, other extracellular proteins, intracellular signaling cascades, non-coding RNAs and chromatin-based molecular alterations. Research on breast cancer EMT/MET aims at delivering biomolecules that can be used diagnostically in cancer pathology and possibly provide ideas for how to improve breast cancer therapy.

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Section: Smad and Non-smad Signaling In Emtmentioning

confidence: 99%

“…Silencing of Akt2 prevents Snail-induced downregulation of Ecadherin. 92 Finally, Iliopoulos and colleagues showed that the miR-200a family regulates E-cadherin repression and EMT. 93 The amount of miR-200a present in a cell was shown to be dependent on the balance between Akt1 and Akt2 expression.…”

Section: Smad and Non-smad Signaling In Emtmentioning

confidence: 99%

Reprogramming during epithelial to mesenchymal transition under the control of TGFβ

Tan¹,

Olsson

Moustakas

2014

Cell Adhesion & Migration

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“…Specific phosphorylation of palladin, an actin bundling protein, by Akt1 led to decreased migration (10). Conversely, Akt2 has been found to promote breast cancer epithelial to mesenchymal transition (EMT) through miR-200 modulation (11) as well as an interaction with Snail1 on the E-cadherin promoter (12). Functional differences in glioma have been slightly variable by using knockdown systems in transformed cells.…”

mentioning

confidence: 99%

Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

Turner¹,

Sun²,

Ji³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

103

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Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAS/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Aktderived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76-gene signature DNA repair panel. Consistently, compared with Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor.Akt | glioma | DNA repair | RCAS/tv-a mouse model

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“…In any case, this specific Akt2 subnuclear localization might facilitate its action on FoxO1 and GSK-3␤, promoting the inactivation of this kinase and the subsequent stabilization of Snail1. Since Snail1 also interacts with and increases Akt2 activity (43), it is possible that it creates a stimulatory loop to further enhance Akt2 activity on nuclear targets that regulate apoptosis. In any case, our results explain how Snail1 is controlled by Notch to regulate EndMT and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Coverslips were incubated with pGSK-3␤ (S9) at 1:50 in blocking buffer (PBS-3% BSA) and rinsed with PBS. To detect Akt1 and Akt2 in the nuclear compartment without cytoplasmic interference, the cells were pretreated with CSK buffer as previously described (43) and analyzed with antibodies against Akt1, Akt2, and lamin B (1:50). Briefly, coverslips were incubated on ice for 5 min with CSK buffer (20 mM HEPES [pH 8], 100 mM KCl, 3 mM MgCl 2 , 300 mM sucrose) containing 0.5% Triton X-100 and rinsed once with CSK buffer without Triton X-100.…”

Section: Methodsmentioning

confidence: 99%

A Switch in Akt Isoforms Is Required for Notch-Induced Snail1 Expression and Protection from Cell Death

Frías

Lambies

Viñas-Castells

et al. 2016

Molecular and Cellular Biology

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b Notch activation in aortic endothelial cells (ECs) takes place at embryonic stages during cardiac valve formation and induces endothelial-to-mesenchymal transition (EndMT). Using aortic ECs, we show here that active Notch expression promotes EndMT, resulting in downregulation of vascular endothelial cadherin (VE-cadherin) and upregulation of mesenchymal genes such as those for fibronectin and Snail1/2. In these cells, transforming growth factor ␤1 exacerbates Notch effects by increasing Snail1 and fibronectin activation. When Notch-downstream pathways were analyzed, we detected an increase in glycogen synthase kinase 3␤ (GSK-3␤) phosphorylation and inactivation that facilitates Snail1 nuclear retention and protein stabilization. However, the total activity of Akt was downregulated. The discrepancy between Akt activity and GSK-3␤ phosphorylation is explained by a Notch-induced switch in the Akt isoforms, whereby Akt1, the predominant isoform expressed in ECs, is decreased and Akt2 transcription is upregulated. Mechanistically, Akt2 induction requires the stimulation of the ␤-catenin/TCF4 transcriptional complex, which activates the Akt2 promoter. Active, phosphorylated Akt2 translocates to the nucleus in Notch-expressing cells, resulting in GSK-3␤ inactivation in this compartment. Akt2, but not Akt1, colocalizes in the nucleus with lamin B in the nuclear envelope. In addition to promoting GSK-3␤ inactivation, Notch downregulates Forkhead box O1 (FoxO1), another Akt2 nuclear substrate. Moreover, Notch protects ECs from oxidative stress-induced apoptosis through an Akt2-and Snail1-dependent mechanism.

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Akt2 interacts with Snail1 in the E-cadherin promoter

Cited by 28 publications

References 47 publications

Reprogramming during epithelial to mesenchymal transition under the control of TGFβ

Reprogramming during epithelial to mesenchymal transition under the control of TGFβ

Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

A Switch in Akt Isoforms Is Required for Notch-Induced Snail1 Expression and Protection from Cell Death

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