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Institute of Endocrine Sciences (A.L., M.F., S.C., E.B., P.B.-P., A.S.), University of Milan, Ospedale Maggiore Instituto di Ricovero e Cura a Carattere Scientifico, and Department of Neurosurgery (M.L.), Istituto Scientifico San Raffaele, Milan 20122, Italy
Address all correspondence and requests for reprints to: Anna Spada, M.D., Institute of Endocrine Sciences, Padiglione Granelli, Via Francesco Sforza, 35, 20122 Milan, Italy. E-mail: anna.spada{at}unimi.it.
The G protein-coupled receptor (GPCR) activation has been demonstrated to affect the ERK1/2 cascade in different cell lines. We investigated the effects of hypothalamic neuropeptides acting via GPCR on this pathway in GH-secreting (GH-oma) and nonsecreting (NFPA) pituitary adenomas. GHRH increased ERK1/2 activity (236 ± 80%) in both gsp- and gsp+ GH-omas, this effect being almost completely abolished by protein kinase C (PKC) blockade. Both GnRH and pituitary adenylate-activating peptide caused a similar PKC-dependent activation of ERK1/2 in most NFPA. Increasing cAMP by forskolin caused a protein kinase A-dependent increase of ERK activity (287 ± 37%) in GH-omas and had no effect in NFPA. ERK cascade blockade in GH-omas did not affect basal and GHRH-stimulated GH release, whereas it totally prevented the 3-fold increase in cyclin D1 protein expression induced by GHRH. In conclusion, this study demonstrated that in pituitary adenomas the activation of GPCR by neurohormones caused a PKC-dependent activation of ERK1/2 cascade that, at least in GH-omas, resulted to be involved in cyclin D1 induction by GHRH. Moreover, a stimulatory effect of the protein kinase A-dependent pathway on ERK1/2 cascade occurred selectively in GH-omas, probably contributing to the mitogenic potential of the cAMP pathway in this cell type.
This work was supported in part by Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST) Grant 2001068427 and Ricerca Corrente funds of Ospedale Maggiore Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) and Istituto Auxologico Italiano IRCCS.
Abbreviations: GH-oma, GH-Secreting pituitary adenoma; GPCR, G protein-coupled receptor; MEK, MAP kinase kinase; NFPA, nonsecreting pituitary adenomas; NS, not significant; PACAP, pituitary adenylate-activating peptide; PKA, protein kinase A; PKC, protein kinase C.
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