Converging signals synergistically activate the LAMC2 promoter and lead to accumulation of the laminin gamma 2 chain in human colon carcinoma cells.
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.
Olsen
Jørgen
J
Department of Medical Biochemistry & Genetics, Biochemistry Laboratory C, University of Copenhagen, The Panum Institute Bldg. 6.4., Blegdamsvej 3, DK-2200N, Denmark. jolsen@biobase.dk
Kirkeby
Lene T
LT
Brorsson
Marianne M
MM
Dabelsteen
Sally
S
Troelsen
Jesper T
JT
Bordoy
Randi
R
Fenger
Kirsten
K
Larsson
Lars-Inge
LI
Simon-Assmann
Patricia
P
D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007797:Laminin / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D020218:Response Elements; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C400567:LAMC2 protein, human; D007797:Laminin; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor