Cu. Pietrzik et al., FROM DIFFERENTIATION TO PROLIFERATION - THE SECRETORY AMYLOID PRECURSOR PROTEIN AS A LOCAL MEDIATOR OF GROWTH IN THYROID EPITHELIAL-CELLS, Proceedings of the National Academy of Sciences of the United Statesof America, 95(4), 1998, pp. 1770-1775
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.