TGF-beta modulates beta-Catenin stability and signaling in mesenchymal proliferations.
Here for the first time we showed, despite the oncogenic mutations in beta-Catenin, that TGF-beta is a modulator of beta-Catenin levels in tumoral fibroblasts as well as non-tumoral fibroblasts. The results show that the TGF-beta pathway is active in desmoids cells and in in situ tumors. A dose dependent increase in beta-Catenin protein levels was observed after TGF-beta treatment in combination with an increased repression of GSK-3beta both in normal and tumoral fibroblasts. TGF-beta stimulation also led to an altered -- up to 5 fold -- transcriptional activity of beta-Catenin responsive promoters, such as IGFBP6 as well as increase of TOPflash activity. TGF-beta stimulation increased cell proliferation and BrdU incorporation 2.5 times. Taken together, we propose that TGF-beta is a modulator of beta-Catenin levels in tumoral fibroblasts and non-tumoral fibroblasts, despite the oncogenic mutations already present in this gene in tumoral fibroblasts of desmoid tumors. This modulation of beta-Catenin levels by TGF-beta may be involved in determining the tumoral phenotype of the cells.
Amini Nik
Saeid
S
Department of Human Genetics, Catholic University of Leuven, Herestraat 49, Leuven, Belgium.
Ebrahim
Rasoul Pour
RP
Van Dam
Kim
K
Cassiman
Jean-Jacques
JJ
Tejpar
Sabine
S
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018222:Desmoid Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000235:genetics; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D018976:Insulin-Like Growth Factor Binding Protein 6; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051176:beta Catenin; D012694:Serine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3