Activation of the canonical beta-catenin pathway by histamine.
Histamine signaling is a principal regulator in a variety of pathophysiological processes including inflammation, gastric acid secretion, neurotransmission, and tumor growth. We report that histamine stimulation causes transactivation of a T cell factor/beta-catenin-responsive construct in HeLa cells and in the SW-480 colon cell line, whereas histamine did not effect transactivation of a construct containing the mutated response construct FOP. On the protein level, histamine treatment increases phosphorylation of glycogen synthase kinase 3-beta in HeLa cells, murine macrophages, and DLD-1, HT-29, and SW-480 colon cell lines. Furthermore, histamine also decreases the phosphorylated beta-catenin content in HeLa cells and murine macrophages. Finally, pharmacological inhibitors of the histamine H1 receptor counteracted histamine-induced T cell factor/beta-catenin-responsive construct transactivation and the dephosphorylation of beta-catenin in HeLa cells and in macrophages. We conclude that the canonical beta-catenin pathway acts downstream of the histamine receptor H1 in a variety of cell types. The observation that inflammatory molecules, like histamine, activate the beta-catenin pathway may provide a molecular explanation for a possible link between inflammation and cancer.
Diks
Sander H
SH
Laboratory for Experimental Internal Medicine, Academic Medical Center, Meibergdreef 9, The Netherlands. S.H.Diks@amc.uva.nl
Hardwick
James C
JC
Diab
Remco M
RM
van Santen
Marije M
MM
Versteeg
Henri H
HH
van Deventer
Sander J H
SJ
Richel
Dick J
DJ
Peppelenbosch
Maikel P
MP
D000469:Alkaline Phosphatase / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D010766:Phosphorylation; D011969:Receptors, Histamine H1 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D011969:Receptors, Histamine H1; D015534:Trans-Activators; D051176:beta Catenin; D006632:Histamine; D008156:Luciferases; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D000469:Alkaline Phosphatase