Cross-talk between Smad and p38 MAPK signalling in transforming growth factor beta signal transduction in human glioblastoma cells.
Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine involved in the regulation of cell proliferation, differentiation, and survival. Malignant tumour cells often do not respond to TGF-beta by growth inhibition, but retain responsiveness to cytokine in regulating extracellular matrix deposition, cell adhesion, and migration. We demonstrated that TGF-beta1 does not affect viability or proliferation of human glioblastoma T98G, but increases transcriptional responses exemplified by induction of MMP-9 expression. TGF-beta receptors were functional in T98G glioblastoma cells leading to SMAD3/SMAD4 nuclear translocation and activation of SMAD-dependent promoter. In parallel, a selective activation of p38 MAPK, and phosphorylation of its substrates: ATF2 and c-Jun proteins were followed by a transient activation of AP-1 transcription factor. Surprisingly, an inhibition of p38 MAPK with a specific inhibitor, SB202190, abolished TGF-inducible activation of Smad-dependent promoter and decreased Smad2 phosphorylation. It suggests an unexpected interaction between Smad and p38 MAPK pathways in TGF-beta1-induced signalling.
Dziembowska
Magdalena
M
Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland.
Danilkiewicz
Malgorzata
M
Wesolowska
Aleksandra
A
Zupanska
Agata
A
Chouaib
Salem
S
Kaminska
Bozena
B
D005909:Glioblastoma / Q000503:physiopathology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D007093:Imidazoles; D011725:Pyridines; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole