title: Cyclic adenosine 3'-5'-monophosphate (cAMP) exerts proliferative and anti-proliferative effects in pituitary cells of different types by activating both cAMP-dependent protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac).
abstract: In the pituitary the activation of cyclic adenosine 3'-5'-monophosphate (cAMP) dependent pathways generates proliferative signals in somatotrophs, whereas in pituitary cells of other lineages its effect remains uncertain. Moreover, the specific role of the two main cAMP effectors, protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac), has not been defined. Aim of this study was to investigate the effect of cAMP on pituitary adenomatous cells proliferation and to identify PKA and Epac differential involvement. We found that cAMP increased DNA synthesis and cyclin D1 expression in somatotropinomas, whereas it reduced both parameters in prolactinomas and nonfunctioning adenomas, these effects being replicated in corresponding cell lines. Moreover, the divergent cAMP effects were mimicked by Epac and PKA analogs, which activated Rap1 and CREB, respectively. In conclusion, we demonstrated that cAMP exerted opposite effects on different pituitary cell types proliferation, these effects being mediated by both Epac and PKA.
authors.affiliation: Endocrine Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Vitali
authors.affiliation: Endocrine Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Peverelli
authors.affiliation: Endocrine Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Giardino
authors.affiliation: Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Locatelli
authors.affiliation: Neurosurgery Unit, IRCCS Humanitas Clinical Institute, Rozzano, Italy.
authors.forename: G B
authors.initials: GB
authors.lastname: Lasio
authors.affiliation: Endocrine Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Beck-Peccoz
authors.affiliation: Endocrine Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Spada
authors.affiliation: Endocrine Unit, IRCCS Humanitas Clinical Institute, University of Milan, Rozzano, Italy. Electronic address: andrea.lania@unimi.it.
authors.forename: A G
authors.initials: AG
authors.lastname: Lania
authors.affiliation: Endocrine Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Mantovani
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D052681:Gonadotrophs / Q000378:metabolism / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D052682:Lactotrophs / Q000378:metabolism / Q000473:pathology; D010902:Pituitary Gland / Q000378:metabolism* / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015175:Prolactinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D021122:Protein Subunits / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D052683:Somatotrophs / Q000378:metabolism / Q000473:pathology; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D020662:Guanine Nucleotide Exchange Factors; D021122:Protein Subunits; C116122:RAPGEF3 protein, human; D019938:Cyclin D1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020827:rap1 GTP-Binding Proteins
keywords: Exchange proteins directly activated by cAMP (Epac); cAMP; cAMP-dependent protein kinase A (PKA)