FROM DIFFERENTIATION TO PROLIFERATION - THE SECRETORY AMYLOID PRECURSOR PROTEIN AS A LOCAL MEDIATOR OF GROWTH IN THYROID EPITHELIAL-CELLS

In various species, thyrotropin (TSH) is known to stimulate both diffe rentiation and proliferation of thyroid follicle cells. This cell type has also been shown to express members of the Alzheimer amyloid precu rsor (APP) protein family and to release the secretory N-terminal doma in of APP (sAPP) in a TSH-dependent fashion, In this study on binding to the cell surfaces, exogenously added recombinant sAPP stimulated ph osphorylation mediated by mitogenactivated protein kinase and effectiv ely evoked proliferation in the rat thyroid epithelial cell line FRTL- 5. To see whether this proliverative effect of sAPP is of physiologica l relevance, we used antisense techniques to selectively inhibit the e xpression of APP and the proteolytic release of sAPP by cells grown in the presence of TSH, The antisense-induced inhibition was detected by immunoblot, immunoprecipitation, and immunocytochemical analyses. Aft er the reduced APP expression and sAPP secretion? we observed a strong suppression of the TSH-induced cell proliferation down to 35%. Recomb inant sAPP but not TSH was able to overcome this antisense effect and to completely restore cell proliferation, indicating that sAPP acts do wnstream of TSH, in that it is released from thyroid epithelial cells during TSH-induced differentiation. We propose that sAPP operates as a n autocrine growth factor mediating the proliferative effect of TSH on neighboring thyroid epithelial cells.