Regulation of thyroid cell proliferation by TSH and other factors: A critical evaluation of in vitro models

TSH via cAMP, and various growth factors, in cooperation with insulin or IG F-I stimulate cell cycle progression and proliferation in various thyrocyte culture systems, including rat thyroid cell lines (FRTL-5,WRT, PC Cl3) and primary cultures of rat, dog, sheep and human thyroid. The available data on cell signaling cascades, cell cycle kinetics, and cell cycle-regulatory proteins are thoroughly and critically reviewed in these experimental syste ms. In most FRTL-5 cells, TSH (cAMP) merely acts as a priming/competence fa ctor amplifying PI3K and MAPK pathway activation and DNA synthesis elicited by insulin/IGF-I. In WRT cells, TSH and insulin/IGF-I can independently ac tivate Ras and PI3K pathways and DNA synthesis. In dog thyroid primary cult ures, TSH (cAMP) does not activate Ras and PI3K and cAMP must be continuous ly elevated by TSH to directly control the progression through G(1) phase. This effect is exerted, at least in part, via the cAMP-dependent activation of the required cyclin D3, itself synthesized in response to insulin/IGF-I . This and other discrepancies show that the mechanistic logics of cell cyc le stimulation by cAMP profoundly diverge in these different in vitro model s of the same cell. Therefore, although these different thyrocyte systems c onstitute interesting models of the wide diversity of possible mechanisms o f cAMP-dependent proliferation in various cell types, extrapolation of in v itro mechanistic data to TSH-dependent goitrogenesis in man can only be acc epted in the cases where independent validation is provided.