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. 2003 Apr 1;371(Pt 1):211–221. doi: 10.1042/BJ20021454

Converging signals synergistically activate the LAMC2 promoter and lead to accumulation of the laminin gamma 2 chain in human colon carcinoma cells.

Jørgen Olsen 1, Lene T Kirkeby 1, Marianne M Brorsson 1, Sally Dabelsteen 1, Jesper T Troelsen 1, Randi Bordoy 1, Kirsten Fenger 1, Lars-Inge Larsson 1, Patricia Simon-Assmann 1
PMCID: PMC1223269  PMID: 12519076

Abstract

The trimeric extracellular matrix molecule laminin-5 and its constituent chains (alpha 3, beta 3, gamma 2) are normally not detectable intracellularly in intestinal epithelial cells but the laminin gamma 2 chain can be detected in cancer cells at the invasive front of a subset of colon carcinomas. These cells are subjected to cytokines such as transforming growth factor beta 1 (TGF-beta 1) and hepatocyte growth factor (HGF), produced by the tumour cells or by the surrounding stromal cells. The purpose of the present work was to investigate whether TGF-beta 1 and HGF, known to stimulate the LAMC2 gene encoding the laminin gamma 2 chain, might synergize to activate the LAMC2 promoter, and to identify the promoter elements involved. We find evidence for synergy between TGF-beta and HGF with respect to laminin gamma 2 chain expression and promoter activation and demonstrate that this requires the 5' activator protein-1 (AP-1) element of the promoter and an additional upstream element which is also responsive to co-expression of the Smad3 protein from the TGF-beta signalling pathway. The transcripts encoding the other laminin-5 chains are not synergistically activated by HGF and TGF-beta. Thus the synergistic activation of the LAMC2 gene is mediated via different cis-elements and results in an overproduction of the laminin gamma 2 chain relative to the other laminin-5 constituent chains. This difference may explain why laminin gamma 2 chains accumulate in the cells at the invasive front of colon carcinomas.

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Selected References

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