PTH2 receptor-mediated inhibitory effect of parathyroid hormone and TIP39 on cell proliferation.
The parathyroid hormone (PTH) has dual mitogenic and inhibitory effects on cell proliferation, depending on the cell type and experimental conditions. PTH can signal via two different receptors, both positively coupled to the adenylyl cyclase/cyclic AMP pathway which can mimic some of the proliferative effects of PTH. We evaluated the role of the type-2 PTH (PTH2) receptor on cell proliferation in clonal human embryonic kidney HEK293 cells stably expressing the human PTH2 receptor. Using a cyclic AMP-responsive gene-reporter, we confirmed that the tuberoinfundibular peptide (TIP39) and various human (h) PTH fragments including hPTH-(1-34) were potent agonists (EC(50) in the range of 0.01-0.3 nM) whereas the bovine (b) PTH peptides b(Tyr(34))PTH-(7-34) and its tryptophan derivative b[D-Trp(12),Tyr(34)]PTH-(7-34) behaved as antagonists (IC(50)=117 and 249 nM, respectively). hPTH-(1-34) produced a dose-dependent inhibition of cell proliferation (EC(50)=8.5+/-0.4 nM) after 3 days and this effect was fully reversed by the tryptophan derivative antagonist. The same effect was observed with TIP39 which caused a 30% maximal inhibition. These findings reveal that PTH2 receptor activation can inhibit cell proliferation and might explain the dual functionality of PTH on cell proliferation.
Misiano
Paola
P
GlaxoSmithKline Pharmaceuticals, Department of Neurobiology Research, Via Zambeletti, 20021 Baranzate di Bollate, Milan, Italy.
Scott
Boyd B
BB
Scheideler
Mark A
MA
Garnier
Martine
M
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D018014:Gene Transfer Techniques; D006801:Humans; D007202:Indicators and Reagents; D008156:Luciferases / Q000378:metabolism; D008163:Luminescent Measurements; D009479:Neuropeptides / Q000494:pharmacology*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D044183:Receptor, Parathyroid Hormone, Type 2 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007202:Indicators and Reagents; D009479:Neuropeptides; D010281:Parathyroid Hormone; D044183:Receptor, Parathyroid Hormone, Type 2; C400136:tuberoinfundibular peptide 39; D000242:Cyclic AMP; D008156:Luciferases