S100A4 negatively regulates β-catenin by inducing the Egr-1-PTEN-Akt-GSK3β degradation pathway

Wonseok Yang, Kee Soo Nam, Ji hyun Ju, Kyung min Lee, Sunhwa Oh, Incheol Shin

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2096-2106
Number of pages11
JournalCellular Signalling
Volume26
Issue number10
DOIs
StatePublished - 2014 Jan 1

Fingerprint

Catenins
Phosphoric Monoester Hydrolases
Breast Neoplasms
Neoplasms
Karyopherins
Genes
Lithium Chloride
Glycogen Synthase Kinases
Nuclear Localization Signals
Tensins
Cell Survival
Down-Regulation
Neoplasm Metastasis
Cell Line

Keywords

  • Akt
  • Breast cancer
  • Egr-1
  • S100A4
  • β-Catenin

Cite this

Yang, Wonseok ; Nam, Kee Soo ; Ju, Ji hyun ; Lee, Kyung min ; Oh, Sunhwa ; Shin, Incheol. / S100A4 negatively regulates β-catenin by inducing the Egr-1-PTEN-Akt-GSK3β degradation pathway. In: Cellular Signalling. 2014 ; Vol. 26, No. 10. pp. 2096-2106.
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S100A4 negatively regulates β-catenin by inducing the Egr-1-PTEN-Akt-GSK3β degradation pathway. / Yang, Wonseok; Nam, Kee Soo; Ju, Ji hyun; Lee, Kyung min; Oh, Sunhwa; Shin, Incheol.

In: Cellular Signalling, Vol. 26, No. 10, 01.01.2014, p. 2096-2106.

Research output: Contribution to journalArticle

TY - JOUR

T1 - S100A4 negatively regulates β-catenin by inducing the Egr-1-PTEN-Akt-GSK3β degradation pathway

AU - Yang, Wonseok

AU - Nam, Kee Soo

AU - Ju, Ji hyun

AU - Lee, Kyung min

AU - Oh, Sunhwa

AU - Shin, Incheol

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AB - 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.

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