K. Suzuki et al., Thyroglobulin regulates follicular function and heterogeneity by suppressing thyroid-specific gene expression, BIOCHIMIE, 81(4), 1999, pp. 329-340
Thyroglobulin (TG) is the primary synthetic product of the thyroid and the
macromolecular precursor of thyroid hormones. TG synthesis, iodination, sto
rage in follicles, and lysosomal degradation can each modulate thyroid horm
one formation and secretion into the circulation. Thyrotropin (TSH), via it
s receptor (the TSHR), increases thyroid hormone levels by upregulating exp
ression of the sodium iodide symporter (NIS), thyroid peroxidase (TPO), and
TG genes. TSH does this by modulating the expression and activity of the t
hyroid-specific transcription factors, thyroid transcription factor (TTF)-1
, TTF-2, and Pax-8, which coordinately regulate NIS, TPO, TG, and the TSHR.
Major histocompatibility complex (MHC) class I gene expression, which is a
lso regulated by TTF-1 and Pax-8 in the thyroid, is simultaneously decrease
d; this maintains self tolerance in the face of TSH-increased gene products
necessary for thyroid hormone formation. We now show that follicular TG, 2
7S > 19S > 12S, counter-regulates TSH-increased thyroid-specific gene trans
cription by suppressing the expression of the TTF-1, TTF-2, and Pax-8 genes
. This decreases expression of the TG, TPO, NIS and TSHR genes, but increas
es class I expression. TG action involves an apical membrane TG-binding pro
tein; however, it acts transcriptionally, targeting, for example, a sequenc
e within 1.15 kb of the start of TTF-1 transcription. TG does not affect ub
iquitous transcription factors regulating TG, TPO, MS and/or TSHR gene expr
ession. TG activity is not duplicated by thyroid hormones or iodide. We hyp
othesize that TG-initiated, transcriptional regulation of thyroid-restricte
d genes is a normal, feedback, compensatory mechanism which regulates folli
cular function, regulates thyroid hormone secretion, and contributes to fol
licular heterogeneity. (C) Societe francaise de biochimie et biologie molec
ulaire / Elsevier, Paris.