PARADOXICAL ACCUMULATION OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P27(KIP1) DURING THE CAMP-DEPENDENT MITOGENIC STIMULATION OF THYROID EPITHELIAL-CELLS

In different systems, cAMP either blocks or promotes cell cycle progre ssion in mid to late G(1) phase. Dog thyroid epithelial cells in prima ry culture constitute a model of positive control of DNA synthesis ini tiation and G(0)-S prereplicative phase progression by cyclic AMP (cAM P) as a second messenger for thyrotropin (TSH), We report here that TS H markedly increases the expression of p27(kip1), the inhibitor of the cell cycle and cyclin-dependent kinases. This effect was prevented by the concomitant administration of the cAMP-independent mitogens, epid ermal growth factor (EGF)+serum. EGF+serum also slightly inhibited the weak basal accumulation of p27(kip1). Nevertheless, in the case of st imulation by TSH alone, the cAMP-dependent cell cycle progression was fully compatible with the enhanced expression of p27(kip1). This obser vation is paradoxical since a decrease of p27(kip1) is generally assoc iated with growth stimulation in other systems, and since a similar cA MP-dependent increase of p29(kip1) in macrophages has been found respo nsible for mid-G(1) cell cycle arrest. The opposite regulation of p27( kip1) in response to TSH or EGF+serum in dog thyroid epithelial cells suggests a major difference at mid to late G(1) stages between cAMP-de pendent and cAMP-independent mitogenic pathways.