Steroids and the scientist
Open accessAbstract
Our interest in nuclear receptors (NRs) originated from early studies on hepatic steroid metabolism. We discovered a new hypothalamo-pituitary-liver axis, imprinted neonatally by androgens and operating through sexually differentiated GH secretory patterns. Male and female patterns have opposite effects on sexually differentiated hepatic genes, explaining sexually dimorphic liver patterns. To further understand steroid action, we purified the glucocorticoid receptor (GR) leading to our discovery of the NR three-domain structure, with separable DNA binding domain and ligand binding domains and a third domain now known to have transcriptional regulatory properties. Knowledge of this domain structure has been immensely important for deciphering NR actions. Using this first purified NR, we collaborated with Keith Yamamoto and first demonstrated specific NR binding to DNA. This also was the first demonstration of a mammalian transcription factor, a breakthrough that led to discovery of NR response elements. In further collaboration with Yamamoto, we cloned the first NR cDNA sequences, leading to cloning of the superfamily of NR genes. With Yamamoto and Kaptein, we determined the first three-dimensional NR structure, that of DNA binding domain. Later work on orphan receptors resulted in the first discovery of: 1) endogenous ligands for an orphan receptor (fatty acids as activators of peroxisomal proliferator-activated receptor alpha); 2) liver X receptor beta (OR-1) and its role in central nervous system cholesterol homeostasis; and 3) estrogen receptor beta, leading to a paradigm shift in understanding of estrogen signaling, of importance in endocrinology, immunology, and oncology and to development of estrogen receptor beta agonists for treatment of autoimmune diseases, prostate disease, depression, and ovulatory dysfunction.
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- Authors
- Gustafsson, J.-A.
- Affiliations
- Department of Medical Nutrition, Karolinska Institutet, Novum, SE-141 86 Huddinge, Sweden
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2005-06-01
- Volume
- 19
- Issue
- 6
- Pages
- 1412-1417
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2158724237
- Cited by
- 19
- References
- 42
- Citations by year
- 2023: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2012: 2
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Karolinska Institutet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- nuclear receptors, steroid hormones, glucocorticoid receptor, androgens, transcription factors, orphan receptors, fatty acid ligands, liver X receptor beta, estrogen receptor beta, estrogen signaling, estrogen receptor beta agonist, autoimmune disease, prostate diseases, depression, ovulatory dysfunction
- MeSH terms
- Animals, Cloning, Molecular, DNA, Endocrinology, Humans, Steroids, Sweden, History, 20th Century
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