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Conditional Overexpression of the Wild-Type G_s as the gsp Oncogene Initiates Chronic Extracellularly Regulated Kinase 1/2 Activation and Hormone Hypersecretion in Pituitary Cell Lines

Unité Mixte de Recherche 6544, Institut Fédératif de Recherche Jean-Roche, Faculté de Médecine Nord, 13916 Marseille cedex 20, France

Address all correspondence and requests for reprints to: C. Gerard, Unité Mixte de Recherche 6544, Institut Fédératif de Recherche Jean-Roche, Faculté de Médecine Nord, Boulevard Pierre Dramard, 13916 Marseille cedex 20, France. E-mail: corinne.gerard{at}univmed.fr.

In pituitary cells, activation of the cAMP pathway by specific G protein-coupled receptors controls differentiative functions and proliferation. Constitutively active forms of the subunit of the heterotrimeric G_s protein resulting from mutations at codon 201 or 227 (gsp oncogene) were first identified in 30–40% of human GH-secreting pituitary adenomas. This rate of occurrence suggests that the gsp oncogene is not responsible for initiating the majority of these tumors. Moreover, there is a large overlap between the clinical phenotypes observed in patients with tumors bearing the gsp oncogene and those devoid of this oncogene. To explore the role of G_s in GH-secreting adenomas, we obtained somatolactotroph GH4C1 cell lines by performing doxycycline-dependent conditional overexpression of the wild-type G_s protein and expression of the gsp oncogene. Although the resulting adenylyl cyclase and cAMP levels were 10-fold lower in the wild-type G_s-overexpressing cell line, a sustained MAPK ERK1/2 activation was observed in both cell lines. Overexpression of the wild-type G_s protein as the gsp oncogene initiated chronic activation of endogenous prolactin synthesis and release, as well as chronic activation of ERK1/2-sensitive human prolactin and GH promoters.