Field of Medical Science and Pharmaceutical ScienceAchievement
Discovery of the nuclear hormone receptor family and its application to drug development

Prof. Ronald M. Evans (USA)
Born: April 17, 1949 (Age: 74)
Professor, Director of Gene Expression Laboratory,
The Salk Institute for Biological Studies

Nuclear receptors that bind fat-soluble hormonesand vitamins
The human body maintains homeostasis through theaction of various hormones. Hormones are secreted into
the blood, and then transported throughout the bodyto reach the cells of their target organs. The hormones
then bind to “receptors” within the cells, and this acts
as a trigger to activate the effects associated with thosehormones.
Hormones come in two types: water-soluble and fat-soluble. Water-soluble hormone receptors are present in cell
membranes, and when a hormone binds with them, thereceptors in the cell membrane transmit information into
the cell.
Meanwhile, thyroid and other fat-soluble hormones passthrough the cell membrane to enter the cell, and can eventravel into the nucleus. That is why it was thought that
fat-soluble hormone receptors would be present withincells, including inside the nucleus, but those receptors
remained unidentified for a long time.
Prof. Ronald Evans was the first researcher in the world
to isolate the receptor for the fat-soluble hormone called
glucocorticoid, and revealed its structure as a nuclear
receptor (Fig. 1).

The functions of the nuclear receptor superfamily
Evans went on to identify a number of new nuclear
receptors since isolating the glucocorticoid receptor. He
found the receptors for estrogen and thyroid hormones, andalso revealed that the receptors for fat-soluble vitamins suchas vitamin D and vitamin A are actually nuclear receptors.
These led to the understanding that these nuclear receptors
are part of a “superfamily” of related molecules with very
similar structures and functions.
Nuclear receptors are activated after binding with ligands(hormones, vitamins, and other substances that bind specificallyto receptors), and regulate the expression of target genes withspecific DNA sequences at the transcription level (Fig.2). Information is transmitted in this way, and this is how hormones andvitamins interact with receptors. In other words, this shows that
nuclear receptors act as receptors for fat-soluble hormones, vitamins, and other ligands, and also act as so-called “transcriptioncontrol factors.”
Prior to Evans’ work, it was not known that all fat-soluble hormones and vitamins transmit information througha basic shared mechanism. There are 48 types of nuclear
receptor within the human body, and his work in clarifying
the overall picture surrounding this nuclear receptor superfamily opened the door to new research possibilities in thefields of molecular biology and endocrinology.

Physiological effects and diseases involving
nuclear receptors
Members of the nuclear receptor superfamily arepresent in every tissue in the human body, and they
control a variety of physiological activities, including
the metabolism, immunity, inflammation, reproduction,bone formation, and cell differentiation and proliferation(Fig. 3). Nuclear receptor functions are associated witha number of diseases, so a number of drugs have beendeveloped to target those nuclear receptors. The UnitedStates Food and Drug Administration (FDA) is responsible for approving drugs in the US, and around 15% of
the drugs it has approved target nuclear receptors.
For example, clarifying the base of activity mediatedby glucocorticoid receptors has led to the developmentof immunosuppressants and other drugs used to treat
various infectious diseases, rheumatoid arthritis, asthma,and more, and these are now being used around theworld. In addition, research into vitamin A and vitamin
D receptors has revealed the effects of fat-soluble
vitamins, which has led to the widespread use of thesevitamins in the treatment of leukemia, osteoporosis,
psoriasis, and other illnesses.

Opening the door to further drug discovery
through an understanding of nuclear receptors
Many members of the nuclear receptor superfamily werereferred to as “orphan receptors” when they were first dis-covered, because the ligands they would bind with were as
yet unknown. Evans isolated a number of orphan receptors,
including estrogen related receptors (ERR), the retinoid X
receptor (RXR), and the peroxisome proliferator-activatedassociated ligands.
with adipocyte differentiation and glucose-lipid metabolism,
Evans not only identified its endogenous ligands (naturally-occurring ligands present in the body), but he also determinedthat thiazolidine derivatives used in the treatment of diabetes
When controlling transcription, nuclear receptors either
activate or suppress transcription by binding to proteins
called “transcription coactivators.” Evans was also able tosuccessfully isolate transcription coactivators like SMRT,
which play an important role in specific organ and tissue
functions. This research led to a better understanding of
the basis of action and clinical application of selective
estrogen receptor modulators (SERM), which are typicallyused in the treatment of post-menopausal osteoporosis, andof anti-cancer drugs used in treating hormone-responsive
cancers (breast cancer, uterine cancer, prostate cancer, etc.)
In these many ways, Prof. Ronald Evans’ success in clarifying the overall picture of the nuclear receptor superfamily
has not only made an immense contribution to academic research, but also to society as a whole, through his research’s
impact on drug discovery, clinical medicine, pharmacology,
and more.