K. Suzuki et al., AUTOREGULATION OF THYROID-SPECIFIC GENE-TRANSCRIPTION BY THYROGLOBULIN, Proceedings of the National Academy of Sciences of the United Statesof America, 95(14), 1998, pp. 8251-8256
Thyroglobulin (TG), the primary synthetic product of the thyroid, is t
he macromolecular precursor of thyroid hormones. TG synthesis, iodinat
ion, storage in follicles, and degradation control thyroid hormone for
mation and secretion into the circulation. Thyrotropin (TSH), via its
receptor (TSHR), increases thyroid hormone levels by upregulating expr
ession of the sodium iodide symporter (NIS), thyroid peroxidase (TPO),
and TG genes. TSH does this by modulating the expression and activity
of several thyroid-specific transcription factors, thyroid transcript
ion factor (TTF)-1, TTF-2, and Pax-8, which coordinately regulate NIS,
TPO, TG, and the TSHR. Major histocompatibility complex class I gene
expression, which also is regulated by TTF-1 and Pax-8 in the thyroid,
is decreased simultaneously. This helps maintain self-tolerance in th
e face of TSH-increased gene products necessary for thyroid hormone fo
rmation. In this report we show that follicular TG counter-regulates T
SH-increased, thyroid-specific gene transcription by suppressing expre
ssion of the TTF-1, TTF-2, and Pax-8 genes. This decreases expression
of the TG, TPO, NIS, and TSHR genes, but increases class I expression.
TG acts transcriptionally, targeting, for example, a sequence within
1.15 kb of the 5' flanking region of TTF-1. TG does not affect ubiquit
ous transcription factors regulating TG, TPO, NIS, and/or TSHR gene ex
pression. The inhibitory effect of TG on gene expression is not duplic
ated by thyroid hormones or iodide and may be mediated by a TG-binding
protein on the apical membrane. We hypothesize that TG-initiated, tra
nscriptional regulation of thyroid-restricted genes is a normal, feedb
ack, compensatory mechanism that limits follicular function and contri
butes to follicular heterogeneity.