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S100A4 negatively regulates β-catenin by inducing the Egr-1-PTEN-Akt-GSK3β degradation pathway
- Source :
- Cellular signalling. 26(10)
- Publication Year :
- 2014
-
Abstract
- S100A4, also known as the mts1 gene, has been reported as an invasive and metastatic marker for many types of cancers. S100A4 interacts with various target genes that affect tumor cell metastasis; however, little is known about cellular signaling pathways elicited by S100A4. In the current study, we demonstrate an inhibitory effect of S100A4 on β-catenin signaling in breast cancer cells. By overexpressing S100A4 in MCF-7, MDA-MB-231 and MDA-MB-453 breast cancer cells, we observed the down-regulation of β-catenin expression and β-catenin-dependent TCF/LEF transcriptional activities. The activity of GSK3β, which phosphorylates β-catenin and induces proteasomal degradation of β-catenin, was increased in S100A4-overexpressing cell lines. Blocking Glycogen Synthase Kinase (GSK3β) activity by lithium chloride or Dvl gene overexpression restored β-catenin expression. We also found that increased GSK3β activity was due to decrease in Akt activity resulting from Egr-1-induced phosphatase and tensin homolog (PTEN) expression. S100A4 induced Egr-1 nuclear localization by increasing the association between Egr-1 and importin-7 and this effect was reduced in S100A4 mutants that harbored a defect in nuclear localization signals. Collectively, we verify herein that S100A4 may act as a tumor suppressor in breast cancers by down-regulating the central signaling axis for tumor cell survival.
- Subjects :
- Cell signaling
Proteasome Endopeptidase Complex
Transcription, Genetic
Dishevelled Proteins
Down-Regulation
Biology
Glycogen Synthase Kinase 3
GSK-3
Cell Movement
Cell Line, Tumor
Tensin
PTEN
Humans
S100 Calcium-Binding Protein A4
Phosphorylation
RNA, Small Interfering
Protein kinase B
beta Catenin
Adaptor Proteins, Signal Transducing
Cell Proliferation
Early Growth Response Protein 1
Cell Nucleus
Glycogen Synthase Kinase 3 beta
S100 Proteins
PTEN Phosphohydrolase
Cell Biology
Phosphoproteins
HEK293 Cells
Cell culture
Catenin
Cancer research
biology.protein
MCF-7 Cells
RNA Interference
Lithium Chloride
Proto-Oncogene Proteins c-akt
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 18733913
- Volume :
- 26
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Cellular signalling
- Accession number :
- edsair.doi.dedup.....04f778a6bdd306807df87aa46a81a707