title: S100A4 negatively regulates β-catenin by inducing the Egr-1-PTEN-Akt-GSK3β degradation pathway.
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.
authors: Department of Life Science, College of Natural Science, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors: Wonseok
authors: W
authors: Yang
authors: Department of Life Science, College of Natural Science, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors: KeeSoo
authors: K
authors: Nam
authors: Department of Life Science, College of Natural Science, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors: Ji-Hyun
authors: JH
authors: Ju
authors: Department of Life Science, College of Natural Science, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors: Kyung-Min
authors: KM
authors: Lee
authors: Department of Life Science, College of Natural Science, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors: Sunhwa
authors: S
authors: Oh
authors: Department of Life Science, College of Natural Science, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea. Electronic address: incheol@hanyang.ac.kr.
authors: Incheol
authors: I
authors: Shin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D000072261:Dishevelled Proteins; D015536:Down-Regulation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D061986:MCF-7 Cells; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D051766:Early Growth Response Protein 1; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D051176:beta Catenin; C077591:S100A4 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D046988:Proteasome Endopeptidase Complex; D018021:Lithium Chloride
keywords: Akt; Breast cancer; Egr-1; S100A4; β-Catenin