Conditional overexpression of the wild-type Gs alpha as the gsp oncogene initiates chronic extracellularly regulated kinase 1/2 activation and hormone hypersecretion in pituitary cell lines.
In pituitary cells, activation of the cAMP pathway by specific G protein-coupled receptors controls differentiative functions and proliferation. Constitutively active forms of the alpha 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)alpha in GH-secreting adenomas, we obtained somatolactotroph GH4C1 cell lines by performing doxycycline-dependent conditional overexpression of the wild-type G(s)alpha 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)alpha-overexpressing cell line, a sustained MAPK ERK1/2 activation was observed in both cell lines. Overexpression of the wild-type G(s)alpha 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.
Romano
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D
Unité Mixte de Recherche 6544, Institut Fédératif de Recherche Jean-Roche, Faculté de Médecine Nord, Boulevard Pierre Dramard, 13916 Marseille cedex 20, France.
Magalon
K
K
Pertuit
M
M
Rasolonjanahary
R
R
Barlier
A
A
Enjalbert
A
A
Gerard
C
C
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002864:Chromogranins; D000242:Cyclic AMP / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D004789:Enzyme Activation; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics; D011388:Prolactin / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D052683:Somatotrophs / Q000201:enzymology / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D019076:Transgenes / Q000187:drug effects
D002864:Chromogranins; D015513:Oncogene Proteins; D011388:Prolactin; D013006:Growth Hormone; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C498643:Gnas protein, rat; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D004318:Doxycycline