Cyclic AMP, the first discovered second messenger of hormone action, elicits cell type-specific effects on proliferation. Proliferation in many cells is inhibited by cAMP, effects mediated in part through interference with Ras-mediated signaling. In endocrine and other cells, cAMP is a mitogen, and in the appropriate cellular context, an oncogene. Mutations leading to constitutive activation of cAMP-mediated signaling have been identified in human pituitary and thyroid tumors. Despite this, relatively little is known regarding how cAMP stimulates proliferation. Our work in thyroid epithelial cells has revealed that cAMP-stimulated proliferation proceeds through divergent pathways, only some of which require PKA activity. The recent discover of cAMP-regulated guanine nucleotide exchange factors for Rap1, a small GTP-binding protein closely related to Ras, establishes that the effects of cAMP are far more divergent than currently appreciated. Crosstalk between cAMP and Ras, and potentially between Ras and Rap, is an important feature of cAMP- mediated mitogenesis. cAMP influences Ras-mediated signaling at points both upstream and downstream from Ras. We are one of very few laboratories that have developed and characterized cellular models in which to investigate cAMP-regulated growth control. The long term goals of our studies are to identify the molecules which participate in cAMP-stimulated cell cycle progression, and to elucidate how cAMP- and Ras-mediated signals are integrated in the control of epithelial cell proliferation. Our immediate goals are to define the contributions of PKA and Ras in the regulation of PI3K activity; to identify the mechanisms through which cAMP elevating agents activate both Ras and Rap, and to elucidate how Ras and PKA cooperatively regulate Rap1 activity. The identification of sites of crosstalk between cAMP and Ras may reveal novel drug targets for future therapeutic intervention. Given the high frequency (ca 100 percent) of thyroid tumors observed at autopsy, identification of growth regulatory circuits targeted by cAMP is an important and exciting area for future investigation.
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