Thyroid hormone and thyroid hormone nuclear receptors: History and present state of art

The present review traces the road leading to discovery of L-thyroxine, thyroid hormone (3,5,3´-triiodo-L-thyronine, T₃) 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. T₃ specific binding sites in the cell nuclei have opened a new era in the field of the thyroid hormone receptors (TRs) discovery. T₃ actions are mediated by high affinity nuclear TRs, TRalpha and TRbeta, which function as T₃-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. T₃ 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 T₃ 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 T₃ receptors, starting from discovery of T3 binding sites in the cell nuclei to revelation of T₃ receptors as T₃-inducible transcription factors in relation to T₃ action at cellular level. It also focuses on milestones of investigation, comprising RXR/TR dimerization, cross-talk between T₃ receptors, and other regulatory pathways within the cell and mainly on genomic action of T₃. This review also focuses on novel directions of investigation on relationships between T₃ receptors and cancer. Based on the update of available literature and the author's experimental experience, it is devoted to clinicians and medical students.