Adrenomedullin stimulates DNA synthesis and cell proliferation via elevation of cAMP in Swiss 3T3 cells.
Our results demonstrate that the novel vasoactive regulatory peptide adrenomedullin is a potent mitogen for Swiss 3T3 cells. Acting via a specific adrenomedullin receptor, it stimulates a dose-dependent increase in DNA synthesis in synergy with insulin. Additionally, adrenomedullin stimulates further progression through the cell cycle resulting in cell proliferation, an effect that was further enhanced by the presence of insulin. Adrenomedullin rapidly induces accumulation of intracellular cAMP but does not stimulate an increase in intracellular Ca2+, activation of protein kinase C, or tyrosine phosphorylation of intracellular substrates. Adrenomedullin-stimulated mitogenesis is markedly enhanced in Swiss 3T3 cells stably transfected with a constitutively activated Gs alpha, which are highly sensitive to agents that elevate cAMP, and is inhibited by the PKA inhibitor H-89. Adrenomedullin is, thus, identified as a novel mitogenic regulatory peptide acting via cAMP.
Imperial Cancer Research Fund, London, UK.
D J
DJ
Withers
H A
HA
Coppock
T
T
Seufferlein
D M
DM
Smith
S R
SR
Bloom
E
E
Rozengurt
D016475:3T3 Cells; D053607:Adrenomedullin; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D010455:Peptides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D019000:Phosphotyrosine / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D014665:Vasodilator Agents / Q000494:pharmacology
D007328:Insulin; D008934:Mitogens; D010455:Peptides; D014665:Vasodilator Agents; D053607:Adrenomedullin; D019000:Phosphotyrosine; D004247:DNA; D000242:Cyclic AMP; D011493:Protein Kinase C; D002118:Calcium