Ras is an almost universal component of signaling pathways in vertebrates, invertebrates and yeast where it plays critical roles in development, proliferation, differentiation and survival. In the twenty years since the first identification of mutated Ras genes in human tumors, intensive effort has been devoted to understanding how Ras promotes neoplastic transformation. What has become clear is that Ras promotes transformation in multiple ways. The effects of Ras are diverse due to the significant complexity of Rasmediated signaling pathways. Mammalian cells express multiple Ras proteins, which localize to discrete membrane microdomains and exhibit differential affinities towards downstream signaling molecules. The existence of a large number of Ras effectors, many of which are members of multi-gene families, together with extensive sites of crosstalk between Ras and other intracellular signaling pathways, further increases the complexity of Ras-mediated signaling.
Mutations in all three cellular Ras genes (H-, K- and N-Ras) have been identified in benign and malignant thyroid tumors. This has generated immense interest in elucidating the cellular consequences of Ras activation in thyroid cells. The recent discovery of B-Raf mutations in thyroid tumors reaffirms the important contribution of Ras-mediated signaling pathways to thyroid cell transformation. Interestingly, the effects of Ras in thyroid cells are unusual in several respects. Unlike primary fibroblasts where expression of activated Ras induces growth arrest, Ras stimulates proliferation in primary human thyrocytes. Recent data suggests that this may be a consequence of cell type specific effects on cell cycle regulatory proteins. Thyroid cells are one of few cellular models where proliferation is positively regulated by cAMP. As discussed below, crosstalk between cAMP and Ras markedly influences the signaling pathways activated by Ras. Indeed, TSH has been shown to modulate the effects of Ras on differentiation, proliferation and survival. The focus of this chapter is on the effects of Ras activation in thyroid cells, including the role of cellular Ras in TSH driven proliferation and the contribution of sustained Ras activity to thyroid cell transformation.
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