cAMP-dependent oncogenic action of Rap1b in the thyroid gland.
cAMP signaling leads to activation and phosphorylation of Rap1b. Using cellular models where cAMP stimulates cell proliferation, we have demonstrated that cAMP-mediated activation, as well as phosphorylation of Rap1b, is critical for cAMP stimulation of DNA synthesis. To determine whether Rap1b stimulates mitogenesis in vivo, we have constructed a transgenic mouse where a constitutively active G12V-Rap1b, flanked by Cre recombinase LoxP sites, is followed by the dominant negative S17N mutant. Employing this novel mouse model, we have switched, in a tissue-specific (thyroid) and temporally controlled manner, the expression of Rap1b from a stimulatory to an inhibitory form. These experiments provide conclusive evidence that Rap1b is oncogenic in the thyroid in ways linked to transduction of the cAMP mitogenic signal.
Department of Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Fernando
F
Ribeiro-Neto
Angelica
A
Leon
Julie
J
Urbani-Brocard
Liguang
L
Lou
Abraham
A
Nyska
Daniel L
DL
Altschuler
D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002277:Carcinoma / Q000473:pathology; D002417:Cattle; D002454:Cell Differentiation; D000242:Cyclic AMP / Q000737:chemistry* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005799:Genes, Dominant; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic; D015398:Signal Transduction; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D019076:Transgenes; D020668:rap GTP-Binding Proteins / Q000096:biosynthesis* / Q000737:chemistry
D013956:Antithyroid Agents; D019394:Ki-67 Antigen; D004247:DNA; D000242:Cyclic AMP; C492136:Rap1b protein, mouse; D020668:rap GTP-Binding Proteins; D001973:Bromodeoxyuridine