Table 3.

Milestones in the search for mechanism of thyroid hormone action.

Year/Period	Milestone
1905	Starling introduces the word hormone and the concept of chemical messengers
1911	Mammalian thyroid extracts shown to induce amphibian metamorphosis
1919	Thyroxine and cortisone extracted and chemically characterized by Kendall
1920–1935	Effects of thyroid hormone on tissue and whole body respiration and metabolic functions
1925–45	Isolation and characterization of pituitary protein hormones
1935–50	Hormone-enzyme interactions thought to explain hormone action
1941–55	Insulin and other hormones shown to regulate transport processes
1955–62	Thyroxine thought to act by uncoupling oxidative phosphorylation
1956	Discovery of cyclic AMP by Sutherland and the concept of “second messenger”
1960	Ecdysteroids induce chromosomal puffing during insect development—first indication of hormone action at the nucleus
1962	Oestradiol shown to bind to nuclear proteins. First, indication of nuclear receptors
1962–66	Steroid and thyroid hormones and retinoids selectively regulate protein synthesis and transcription
1975–85	Protein hormone receptors located in cell membranes identified as homologues of c-erbB oncogene; protein phosphorylation cascades identified
1979–89	Steroid/thyroid/retinoid receptors cloned as a large family of c-erbA-related transcription factors interacting with target genes and modifying chromatin structure
1990s	Crystal structures for many hormone receptors and partners. Transgenesis and mutagenesis of receptors in vivo
1996	Coactivators and corepressors modulate gene expression by TR and other nuclear receptors
1998	Phosphorylation, acetylation, and methylation of TR and other nuclear receptors, histones, and chromosomal proteins
2002–2010	Convergence of hormonal signals via membrane and nuclear receptors. Emergence of concepts of systems biology, bioinformatics and gene, and metabolic networking applicable to hormone action