Akt/protein kinase B promotes survival and hormone-independent proliferation of thyroid cells in the absence of dedifferentiating and transforming effects

The Akt/protein kinase B serine/threonine kinase is a downstream effector o f phosphoinositide 3-kinase (PI3K). Akt is an important component of mitoge nic and antiapoptotic signaling pathways and is implicated in neoplastic tr ansformation. Thyroid cells in culture retain a differentiated phenotype co nsisting of epithelial fell morphology and the expression of several tissue -specific genes. The survival and proliferation of these cells depend on th yrotropin and a mixture of five additional hormones that includes insulin. The regulation of proliferation and the expression of the thyroid different iation program are intimately connected processes. As a result, oncogenes t hat induce hormone-independent proliferation invariably impair the expressi on of the thyroid-specific differentiation markers, Given that thyrotropin and insulin stimulate Akt activation in thyroid cells, we set out to determ ine the effects of Akt on thyroid cell proliferation, survival, and differe ntiation. To this end, we expressed constitutively active myristylated Akt (mgrAkt) in PC Cl 3 thyroid cells. The myrAkt-expressing cells continued to proliferate, even in the absence of hormones, and they were resistant to p rogrammed cell death induced by starvation. These effects were paralleled b y the induction of the G(1) cyclins D3 and E and by the inhibition of induc tion of the proapoptotic Fas, Fas ligand, and BAD genes in starved cells. H owever, in marked contrast with several other oncogenes, myrAkt did not int erfere with the expression of thyroid differentiation functions. These resu lts unveil the existence of an Akt-triggered thyroid cell pathway that modu lates proliferation and survival without affecting the expression of the th yroid cell differentiated phenotype.