Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
Endocr Regul. 2021 May 21;55(2):103-119. doi: 10.2478/enr-2021-0012.
The present review traces the road leading to discovery of L-thyroxine, thyroid hormone (3,5,3´-triiodo-L-thyronine, T) and its cognate nuclear receptors. Thyroid hormone is a pleio-tropic regulator of growth, differentiation, and tissue homeostasis in higher organisms. The major site of the thyroid hormone action is predominantly a cell nucleus. T specific binding sites in the cell nuclei have opened a new era in the field of the thyroid hormone receptors (TRs) discovery. T actions are mediated by high affinity nuclear TRs, TRalpha and TRbeta, which function as T-activated transcription factors playing an essential role as transcription-modulating proteins affecting the transcriptional responses in target genes. Discovery and characterization of nuclear retinoid X receptors (RXRs), which form with TRs a heterodimer RXR/TR, positioned RXRs at the epicenter of molecular endocrinology. Transcriptional control via nuclear RXR/TR heterodimer represents a direct action of thyroid hormone. T plays a crucial role in the development of brain, it exerts significant effects on the cardiovascular system, skeletal muscle contractile function, bone development and growth, both female and male reproductive systems, and skin. It plays an important role in maintaining the hepatic, kidney and intestine homeostasis and in pancreas, it stimulates the beta-cell proliferation and survival. The TRs cross-talk with other signaling pathways intensifies the T action at cellular level. The role of thyroid hormone in human cancers, acting via its cognate nuclear receptors, has not been fully elucidated yet. This review is aimed to describe the history of T receptors, starting from discovery of T3 binding sites in the cell nuclei to revelation of T receptors as T-inducible transcription factors in relation to T action at cellular level. It also focuses on milestones of investigation, comprising RXR/TR dimerization, cross-talk between T receptors, and other regulatory pathways within the cell and mainly on genomic action of T. This review also focuses on novel directions of investigation on relationships between T receptors and cancer. Based on the update of available literature and the author's experimental experience, it is devoted to clinicians and medical students.
本文追溯了发现左旋甲状腺素、甲状腺激素（3,5,3´-三碘-L-甲状腺原氨酸，T）及其同源核受体的历程。甲状腺激素是高等生物生长、分化和组织稳态的多效调节剂。甲状腺激素作用的主要部位主要在细胞核内。细胞核内 T 特异性结合位点开创了甲状腺激素受体（TR）发现领域的新纪元。T 作用是由高亲和力核 TR、TRα 和 TRβ 介导的，它们作为 T 激活的转录因子发挥作用，作为转录调节蛋白，影响靶基因的转录反应。核视黄酸 X 受体（RXR）的发现和特征，其与 TR 形成 RXR/TR 异二聚体，将 RXR 置于分子内分泌学的中心。通过核 RXR/TR 异二聚体的转录控制代表了甲状腺激素的直接作用。T 在大脑发育中起着至关重要的作用，它对心血管系统、骨骼肌收缩功能、骨骼发育和生长、女性和男性生殖系统以及皮肤都有显著影响。它在维持肝脏、肾脏和肠道稳态以及在胰腺中发挥重要作用，刺激β细胞增殖和存活。TR 与其他信号通路的相互作用增强了 T 在细胞水平上的作用。甲状腺激素在人类癌症中的作用，通过其同源核受体发挥作用，尚未完全阐明。本文旨在描述 T 受体的历史，从细胞核中 T3 结合位点的发现开始，到揭示 T 受体作为 T 诱导的转录因子与细胞水平的 T 作用相关。它还侧重于研究的里程碑，包括 RXR/TR 二聚化、T 受体之间的串扰以及细胞内的其他调节途径，主要是 T 的基因组作用。本文还侧重于 T 受体与癌症之间关系的新研究方向。基于现有文献的更新和作者的实验经验，本文致力于临床医生和医学生。
