Activation of NF‐κB by extracellular S100A4: Analysis of signal transduction mechanisms and identification of target genes
Open Access
- 11 June 2008
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 123 (6), 1301-1310
- https://doi.org/10.1002/ijc.23617
Abstract
The metastasis-promoting protein S100A4 stimulates metastatic progression through both intracellular and extracellular functions. Extracellular activities of S100A4 include stimulation of angiogenesis, regulation of cell death and increased cell motility and invasion, but the exact molecular mechanisms by which extracellular S100A4 exerts these effects are incompletely elucidated. The aim of the present study was to characterize S100A4-induced signal transduction mechanisms and to identify S100A4 target genes. We demonstrate that extracellular S100A4 activates the transcription factor NF-κB in a subset of human cancer cell lines through induction of phosphorylation and subsequent degradation of the NF-κB inhibitor IκBα. Concomitantly, S100A4 induced a sustained activation of the MAP kinase JNK, whereas no increased activity of the MAP kinases p38 or ERK was observed. Microarray analyses identified 136 genes as being significantly regulated by S100A4 treatment, and potentially interesting S100A4-induced gene products include IκBα, p53, ephrin-A1 and optineurin. Increased expression of ephrin-A1 and optineurin was validated using RT-PCR, Western blotting and functional assays. Furthermore, S100A4-stimulated transcription of these target genes was dependent on activation of the NF-κB pathway. In conclusion, these findings contribute to the understanding of the complex molecular mechanisms responsible for the diverse biological functions of extracellular S100A4, and provide further evidence of how S100A4 may stimulate metastatic progression.Keywords
This publication has 57 references indexed in Scilit:
- Interferon-γ-Induced Suppression of S100A4 Transcription Is Mediated by the Class II TransactivatorTumor Biology, 2007
- Ephrin-A1 Facilitates Mammary Tumor Metastasis through an Angiogenesis-Dependent Mechanism Mediated by EphA Receptor and Vascular Endothelial Growth Factor in MiceCancer Research, 2006
- S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9Proceedings of the National Academy of Sciences of the United States of America, 2006
- Nuclear factor-κB in cancer development and progressionNature, 2006
- Identification of TNF-α-responsive NF-κB p65-binding element in the distal promoter of the mouse serine protease inhibitorSerpinE2FEBS Letters, 2006
- Molecular Mechanisms of Ca2+ Signaling in Neurons Induced by the S100A4 ProteinMolecular and Cellular Biology, 2006
- Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin FormationPublished by Elsevier BV ,2005
- S100P Stimulates Cell Proliferation and Survival via Receptor for Activated Glycation End Products (RAGE)Published by Elsevier BV ,2004
- FIP-2, an IκB-Kinase-γ-Related Protein, Is Associated with the Golgi Apparatus and Translocates to the Marginal Band during Chicken Erythroblast DifferentiationExperimental Cell Research, 2002
- Expression of antisense RNA to S100A4 gene encoding an S100-related calcium-binding protein suppresses metastatic potential of high-metastatic Lewis lung carcinoma cellsOncogene, 1997