Molecular Genetics of Steroid and Thyroid 
Hormone Receptors 
Ronald M. Evans, Ph.D. — Investigator 
Dr. Evans is also Professor at the Gene Expression Laboratory of the Salk Institute for Biological Studies 
and Adjunct Professor in the Departments of Biology and Biomedical Sciences at the University of Cali- 
fornia, San Diego. He received his Ph.D. degree in microbiology and immunology from the University of 
California School of Medicine, Los Angeles. After postdoctoral training with James Darnell at the Rocke- 
feller University, he joined the faculty of the Salk Institute. Dr. Evans is a member of the National Academy 
of Sciences. His research interests are in developmental and inducible regulation of gene expression. 
AN understanding of the mechanisms by 
which apparently distinct regulatory sys- 
tems integrate to modulate body function and be- 
havior poses one of the most important chal- 
lenges of modern biology. Hence we have 
focused our attention on the action of steroid, 
retinoid, and thyroid hormones in regulatory cel- 
lular and organ physiology. This field has under- 
gone an extraordinary development in the last 
several years as a consequence of the cloning and 
sequencing of the genes encoding the receptors 
for these hormones in target cells. 
It has been demonstrated that these receptors 
are all structurally related and constitute a super- 
family of nuclear regulatory proteins that are ca- 
pable of modulating gene expression in a ligand- 
dependent fashion. One challenge is to define 
each receptor's molecular properties that deter- 
mine its interactions with the transcription ma- 
chinery regulating gene expression. Another 
challenge is to elucidate the contributions of indi- 
vidual regulatory systems to the integrated and 
complex processes associated with cell growth, 
differentiation, and organ function. 
The Glucocorticoid Regulatory Network 
The glucocorticoid receptor (GR) is well char- 
acterized as a potent activator of transcription. 
More recently the GR has also been shown to re- 
press expression of a variety of genes in response 
to hormones. Glucocorticoids, in addition to 
their inductive effects on specific genes, inhibit 
proliferation of a variety of cultured cell lines 
and oppose the action of lymphokines in the acti- 
vation of T cells. T cell activation is in part me- 
diated by activation of Jun/AP-1, which is a 
member of the class of nuclear proteins encoded 
by proto-oncogenes and a factor in diverse 
aspects of cell growth, differentiation, and 
development. 
We have provided evidence that the GR and 
Jun/AP-1 can reciprocally repress each other's 
transcriptional activation and that this inhibition 
is a consequence of protein-protein interaction. 
The interaction of two distinct regulatory pro- 
teins, referred to as "cross-coupling," has several 
important implications. First, it provides a molec- 
ular framework for understanding the opposing 
effects of growth factors and steroid hormones. 
Growth factors stimulate cellular division, 
whereas steroid hormones inhibit cell division 
while promoting differentiation. 
Perhaps the most intriguing aspect of cross- 
coupling is that it allows interaction of distinct 
classes of transcription factors prior to their in- 
teraction with target DNA sequences. Thus the 
GR prevents AP- 1 from binding to DNA and acti- 
vating a downstream set of target genes. Accord- 
ingly, glucocorticoids indirectly regulate the 
AP- 1 gene network by modulating the DNA-bind- 
ing properties of Jun/AP-1. Although glucocorti- 
coids are thought, classically, to regulate target 
genes by promoting the receptor to bind their 
DNA, cross-coupling allows steroid regulation of 
the AP- 1 -responsive genes, but in a DNA-indepen- 
dent fashion. This DNA-dependent pathway is a 
novel mechanism for steroid control of gene 
expression. 
A Novel Retinoic Acid Response Pathway 
The retinoids make up a group of compounds 
that include retinoic acid, retinol (vitamin A), 
and a series of natural and synthetic derivatives 
that exen profound effects on development and 
differentiation in a wide variety of systems. Reti- 
noic acid has also been shown to induce the tran- 
scription of several genes, supporting the hy- 
pothesis that it has functions analogous to those 
of steroid and thyroid hormones. In previous stud- 
ies we described the cloning and characterization 
of a retinoic acid-dependent transcription factor, 
referred to as RARa. Additional RAR-related genes 
have been isolated, and at least three different 
RAR subtypes (a, ^, and 7) are now known in 
mice and humans. 
Retinoic acid receptors share homology with 
the superfamily of steroid and thyroid hormone 
receptors and have been shown to regulate spe- 
cific gene expression by a similar ligand-depen- 
dent mechanism. Complicating these observa- 
tions is our recent identification of a group of 
receptors termed RXRs (retinoid X receptors). 
127 
