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S100A4 negatively regulates beta-catenin by inducing the Egr-1-PTEN-Akt-GSK3 beta degradation pathway

Title
S100A4 negatively regulates beta-catenin by inducing the Egr-1-PTEN-Akt-GSK3 beta degradation pathway
Author
신인철
Keywords
S100A4; beta-Catenin; Egr-1; Akt; Breast cancer
Issue Date
2014-10
Publisher
Elsevier Science INC
Citation
Cellular Signalling, 2014, 26(10), P.2096-2106
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 beta-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 beta-catenin expression and beta-catenin-dependent TCF/LEF transcriptional activities. The activity of GSK3 beta, which phosphorylates beta-catenin and induces proteasomal degradation of beta-catenin, was increased in S100A4-overexpressing cell lines. Blocking Glycogen Synthase Kinase (GSK3 beta) activity by lithium chloride or Dvl gene overexpression restored beta-catenin expression. We also found that increased GSK3 beta activity was due to decrease in Ala 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. (C) 2014 Elsevier Inc. All rights reserved.
URI
https://www.sciencedirect.com/science/article/pii/S0898656814002022?via%3Dihub
ISBN
1873-3913
ISSN
0898-6568
DOI
10.1016/j.cellsig.2014.06.007
Appears in Collections:
COLLEGE OF NATURAL SCIENCES[S](자연과학대학) > LIFE SCIENCE(생명과학과) > Articles
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