Cyclic AMP signaling in the hormonal control of proliferation and differentiation

Cyclic adenosine 3′ 5′ monophosphate (cAMP) was the first identified second messenger of hormone action. Although cAMP was initially classified as an inhibitor of cellular proliferation, there are many cell types in which cAMP stimulates cell cycle progression. The mechanisms by which cAMP stimulates proliferation, unlike its growth inhibitory effects, have not been well studied. In Wistar rat-thyroid cells, thyrotropin (TSH), acting through elevations in cAMP, stimulates proliferation and expression of the differentiated phenotype. PKA activity is essential for the mitogenic, effects of cAMP. Ras is also required for cAMP-stimulated proliferation; however, cAMP downregulates signaling through the Raf-1 effector pathway in these cells, as it does in many other systems. This may be important for cAMP effects on differentiation, as Ras impairs thyroid-specific gene expression, an effect mediated at least in part by Raf-1. We believe that cAMP functions as a molecular switch to divert Ras signals away from Raf-1 and to alternate effectors capable of transducing a mitogenic signal that is compatible with differentiation. These studies reveal that cAMP signals diverge to include PKA-dependent (and PI3K-independent) pathways to mTOR/p70s6k and PKA-independent pathways to PI3K/Akt/Rac1. Both signaling pathways are required for the mitogenic effects of cAMP in WRT cells, as interference with mTOR/p70s6k, PI3K, or Rac1 represses cAMP-stimulated DNA synthesis. Studies in additional cell types in which cAMP is mitogenic (Swiss3T3, Schwann), as well as in cells where cAMP fails to stimulate proliferation (NIH3T3, REF52), reveal a correlation between cAMP effects on mTOR/p70s6k and Akt activities and its effects on cell cycle progression. This suggests a potential conserved mechanism through which cAMP stimulates cell cycle progression. In WRT cells, activation of PI3K, including that induced by RasC40, an effector mutant that preferentially interacts with PI3K stimulates both mTOR/p70s6k and Akt activities and induces TSH-independent proliferation. Notably, cAMP does not impair the effects of RasC40 and, conversely, RasC40 does not inhibit cAMP-stimulated differentiation. These findings indicate that Ras signaling through PI3K, unlike that through Raf-1, is compatible with the dual role of cAMP in thyroid proliferation and differentiation