Antifolate/folate-activated HGF/c-Met signalling pathways in mouse kidneys-the putative role of their downstream effectors in cross-talk with androgen receptor.
This in vivo study of mouse kidneys was focused on the identification of protein mediators involved in the cross-talk between two signalling pathways. One pathway was triggered by testosterone via an androgen receptor, AR, and the other induced by CB 3717/folate via HGF, and its membrane receptor c-Met. Sequential activation of these pathways leads to a drastic decrease of testosterone-induced ornithine decarboxylase, ODC, expression. We proved that CB 3717/folate-induced ODC expression is Akt-dependent. CB 3717/folate activates Akt and ERK1/2 kinases, PTEN phosphatase and also up-regulates cyclin D2 and PCNA, but decreases GSK3beta and cyclin D1 protein levels. Testosterone activation of AR induces GSK3beta and PTEN. Results of the sequential activation of the studied signalling pathways suggest that Akt, GSK3beta and possibly ERK1/2 kinases may participate in the negative cross-talk and attenuation of AR transactivity, while the involvement of PTEN and cyclin D1 seems to be doubtful.
Dudkowska
Magdalena
M
Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
Bajer
Seweryn
S
Jaworski
Tomasz
T
Zielińska
Joanna
J
Manteuffel-Cymborowska
Małgorzata
M
Grzelakowska-Sztabert
Barbara
B
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009955:Ornithine Decarboxylase / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D020239:Receptor Cross-Talk; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013739:Testosterone / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D005493:Folic Acid Antagonists; D018809:Proliferating Cell Nuclear Antigen; D011799:Quinazolines; D011944:Receptors, Androgen; D013739:Testosterone; D017228:Hepatocyte Growth Factor; C031662:CB 3717; D005492:Folic Acid; D019859:Proto-Oncogene Proteins c-met; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D009955:Ornithine Decarboxylase; D000077191:Wortmannin