Activation of NF-kappaB by extracellular S100A4: analysis of signal transduction mechanisms and identification of target genes.

Full 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-kappaB in a subset of human cancer cell lines through induction of phosphorylation and subsequent degradation of the NF-kappaB inhibitor IkappaBalpha. 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 IkappaBalpha, 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-kappaB 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.Copyright 2008 Wiley-Liss, Inc.

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Author information

Author/s: Boye, Kjetil (K); Grotterød, Ida (I); Aasheim, Hans-Christian (HC); Hovig, Eivind (E); Maelandsmo, Gunhild M (GM);

Affiliation: Department of Tumor Biology, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, N-0310 Oslo, Norway. kjetil.boye(-atsign-)rr-research.no

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: International journal of cancer. Journal international du cancer (Int J Cancer), published in United States. (Language: eng)

Reference: 2008-Sep; vol 123 (issue 6) : pp 1301-10

Dates: Created 2008/07/23; Completed 2008/08/22;

PMID: 18548584, status: MEDLINE (last retrieval date: 11/6/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Blotting, Western
Cell Line, Tumor
Disease Progression
Electrophoretic Mobility Shift Assay
Enzyme Activation - physiology
Gene Expression
Humans

Humans
NF-kappa B - metabolism
Neoplasms - metabolism
Oligonucleotide Array Sequence Analysis
Reverse Transcriptase Polymerase Chain Reaction
S100 Proteins - metabolism
Signal Transduction - physiology

Associated Chemicals: NF-kappa B (0) ; S100 Proteins (0) ; S100A4 protein, human (142662-27-9)

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