Suzuki K, Mori A, Lavaroni S, Ulianich L, Miyagi E, Saito J, Nakazato M, Pietrarelli M, Shafran N, Grassadonia A, Kim W B, Consiglio E, Formisano S, Kohn L D
Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1800, USA.
Biochimie. 1999 Apr;81(4):329-40. doi: 10.1016/s0300-9084(99)80078-9.
Thyroglobulin (TG) is the primary synthetic product of the thyroid and the macromolecular precursor of thyroid hormones. TG synthesis, iodination, storage in follicles, and lysosomal degradation can each modulate thyroid hormone formation and secretion into the circulation. Thyrotropin (TSH), via its receptor (the TSHR), increases thyroid hormone levels by upregulating expression of the sodium iodide symporter (NIS), thyroid peroxidase (TPO), and TG genes. TSH does this by modulating the expression and activity of the thyroid-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 also regulated by TTF-1 and Pax-8 in the thyroid, is simultaneously decreased; this maintains self tolerance in the face of TSH-increased gene products necessary for thyroid hormone formation. We now show that follicular TG, 27S > 19S > 12S, counter-regulates TSH-increased thyroid-specific gene transcription 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 increases class I expression. TG action involves an apical membrane TG-binding protein; however, it acts transcriptionally, targeting, for example, a sequence within 1.15 kb of the start of TTF-1 transcription. TG does not affect ubiquitous transcription factors regulating TG, TPO, NIS and/or TSHR gene expression. TG activity is not duplicated by thyroid hormones or iodide. We hypothesize that TG-initiated, transcriptional regulation of thyroid-restricted genes is a normal, feedback, compensatory mechanism which regulates follicular function, regulates thyroid hormone secretion, and contributes to follicular heterogeneity.
甲状腺球蛋白（TG）是甲状腺的主要合成产物以及甲状腺激素的大分子前体。TG的合成、碘化、在滤泡中的储存以及溶酶体降解均可调节甲状腺激素的形成及分泌进入循环系统。促甲状腺激素（TSH）通过其受体（TSHR），上调钠碘同向转运体（NIS）、甲状腺过氧化物酶（TPO）及TG基因的表达，从而提高甲状腺激素水平。TSH通过调节甲状腺特异性转录因子甲状腺转录因子（TTF）-1、TTF-2及Pax-8的表达和活性来实现这一作用，这些转录因子协同调节NIS、TPO、TG及TSHR。甲状腺中由TTF-1和Pax-8调节的主要组织相容性复合体（MHC）I类基因表达同时降低；这在面对TSH增加的甲状腺激素形成所需基因产物时维持自身耐受性。我们现在发现，滤泡TG（27S > 19S > 12S）通过抑制TTF-1、TTF-2及Pax-8基因的表达来反向调节TSH增加的甲状腺特异性基因转录。这降低了TG、TPO、NIS及TSHR基因的表达，但增加了I类基因的表达。TG的作用涉及顶端膜TG结合蛋白；然而，它通过转录发挥作用，例如靶向TTF-1转录起始点1.15 kb内的一个序列。TG不影响调节TG、TPO、NIS和/或TSHR基因表达的普遍转录因子。甲状腺激素或碘不会重复TG的活性。我们推测，TG启动的对甲状腺限制性基因的转录调节是一种正常的反馈补偿机制，可调节滤泡功能、调节甲状腺激素分泌并导致滤泡异质性。
