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Abstract
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.
Highlights
CAMP can either stimulate or inhibit cell proliferation, depending on the cell type and context [8, 9], and a striking parallel exists between the action of cAMP and Rap1b on cell proliferation
Whereas Rap1 is inhibitory in model systems where cAMP inhibits cell proliferation [10, 11], we demonstrated that Rap1b stimulates mitogenesis in specific cells where cAMP is a genuine stimulator of cell proliferation [12, 13]
We have proposed that Rap action on mitogenesis depends on cell-specific signal transduction programs such that Rap1b, like cAMP, can either stimulate or inhibit cell proliferation, i.e. that Rap can be viewed as a conditional oncogene
Summary
CAMP can either stimulate or inhibit cell proliferation, depending on the cell type and context [8, 9], and a striking parallel exists between the action of cAMP and Rap1b on cell proliferation. Cre-mediated recombination is expected to occur in every tissue, because of the ubiquitous expression of CMVCRE-ER-Tx, the G12V- to S17N-Rap1b switch only occurs in thyrocytes because of the use of a thyroid-specific promoter in the Rap1bV12-LoxP-N17 mice.
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