Molecular Biology of Steroid and Nuclear Hormone Receptors

329 Pages·1998·9.38 MB·English

by  Didier Picard (auth.), Leonard P. Freedman (eds.)

Progress in Gene Expression
Series Editor
Michael Karin
Department of Pharmacology
School of Medicine
University of California, San Diego
La Jolla, CA 92093-0636
Books in the Series:
Gene Expression: General and Cell-Type-Specific
M. Karin, editor
ISBN 0-8176-3605-6
Inducible Gene Expression, Volume I: Environmental Stresses and Nutrients
P. A. Baeuerle, editor
ISBN 0-8176-3728-1
Inducible Gene Expression, Volume II: Hormonal Signals
P. A. Baeuerle, editor
ISBN 0-8176-3734-6
Oncogenes as Transcriptional Regulators, Volume 1: Retroviral Oncogenes
M. Yaniv and J. Ghysdael, editors
ISBN 3-7643-5486-0
Oncogenes as Transcriptional Regulators, Volume II: Cell Cycle Regulators
and Chromosomal Translocation Products
M. Yaniv and J. Ghysdael, editors
ISBN 3-7643-5709-6
Molecular Biology of Steroid and Nuclear Hormone Receptors
L. Freedman, editor
ISBN 0-8176-3952-7
Molecular Biology
of Steroid and Nuclear
Hormone Receptors
Leonard P. Freedman
Editor
Springer Science+Business Media, LLC
Leonard P. Freedman
CeH Biology and Genetics
Memorial Sloan-Kettering Cancer Center
New York, NY 10021
Library of Congress Cataloging In-Publication Data
Molecular biology of steroid and nuclear honnone receptors / Leonard
P. Freedman, editor.
p. cm. -- (Progress in gene expression)
Includes bibliographical references and index.
ISBN 978-1-4612-7271-7 ISBN 978-1-4612-1764-0 (eBook)
DOI 10.1007/978-1-4612-1764-0
1. Honnone receptors. 2. Steroid honnones--Receptors.
3. Transcription factors. 1. Freedman, Leonard P., 1958-
II. Series.
QP571.7.M65 1997
573.4'48845--dc21 97-21837
CIP
$®
Printed on acid-free paper
© Springer Science+Business Media New York 1998
Originally published by Birkhliuser Boston in 1998
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Contents
Foreword ............................................................................................................ vii
Series Preface ...................................................................................................... xi
Preface .............................................................................................................. xiii
List of Contributors ............................................................................................ xv
1. The Role of Heat Shock Proteins in the Regulation of Steroid
Receptor Function
Didier Picard. ................................................................................................. 1
2. Subcellular and Subnuclear Trafficking of Steroid Receptors
Donald B. DeFranco ...................................................................................... 19
3. Structure and Function of the Steroid and Nuclear Receptor
Ligand-Binding Domain
S. Stoney Simons, Jr. ....................................................................................... 35
4. Structure and Function of the Steroid and Nuclear Receptor DNA
Binding Domain
Fraydoon Rastinejad. ................................................................................... 105
5. Modulation of SteroidlNuclear Receptor Dimerization and DNA Binding
by Ligands
Boris Cheskis and Leonard Freedman. ........................................................ 133
6. Molecular Mechanisms of Nuclear-Receptor-Mediated
Transcriptional Activation and Basal Repression
Milan K. Bagchi. .......................................................................................... 159
7. Transcriptional Cross-Talk by Steroid Hormone Receptors
Peter Berrlich and Martin Gottlicher. ......................................................... 191
vi Contents
8. Chromatin and Steroid-Receptor-Mediated Transcription
Catherine E. Watson and Trevor K. Archer. .................................................. 209
9. Regulation of Glucocorticoid and Estrogen Receptor Activity by
Phosphorylation
Michael J. Garabedian, Inez Rogatsky, Adam Hittelman,
Roland Knoblauch, Janet Trowbridge, and Marija Krstic ............................ 237
10. Monomeric Nuclear Receptors
Mitchell A. Lazar and Heather P. Harding ................................................. 261
11. Orphan Nuclear Receptors and Their Ligands
Barry Marc Forman ............................................................... ;. ................... 281
Foreword
Intracellular Receptors:
New Instruments for a Symphony of Signals
In the late eighteenth century, it was proposed on theoretical grounds that each of
the body's organs, beginning with the brain, must be "a factory and laboratory of a
specific humor which it returns to the blood", and that these circulating signals "are
indispensable for the life of the whole" (Bordeu 1775). During the nineteenth cen
tury, some remarkable physiological experiments revealed the actions of humoral
factors that affected the for and function of multiple tissues, organs and organ sys
tems within the body (Berthold 1849); much later, the chemical and molecular na
ture of some of those factors was determined.
Against this deep historical backdrop of the founding studies of intercellular
signaling, molecular biology sprang into existence a mere forty years ago, rooted in
the revelation of regulable gene expression in bacteria. But contemporaneous with
those classical analyses of transcriptional regulation of the lactose operon, the mod
em era of signal transduction was inaugurated by the identification of cAMP as a
second messenger ---an intracellular mediator of hormonal activation of glycogen
catabolism (Sutherland and RaIl 1960). Later in that same decade, it emerged that
cAMP is a critical signal not only in metazoans, but even in bacteria, where it serves
an analogous function as a critical switch that activates expression of genes re
quired for catabolism of complex carbon sources, including those of the lactose
operon. Indeed, Tomkins proposed the existence of a "metabolic code" in which
certain small molecules acquire "symbolic value", representing and thereby evok
ing global physiological states, and that these symbolic values are stabilized in evo
lution by selective forces similar to those that maintain the near-universality of the
genetic code (Tomkins 1975).
Of course, the linkage between signal transduction and transcriptional regula
tion is far more profound than their shared histories. Transcriptional regulatory
factors are the endpoints of many, probably most, signal transduction pathways --
that is, signaling typically triggers specific changes in gene expression. And
nowhere is that linkage more direct than with the molecules whose signals are me
diated by proteins encoded by a gene superfamily commonly termed the nuclear
receptors, or, in a broader nomenclature that I favor, the intracellular receptors (IRs).
These receptors were first described in the 1960s in studies showing that radio
labeled estradiol is bound selectively in target cells --- specifically, saturably and
noncovalently --- to a protein recovered initially in the cytosol and subsequently in
the nuclear fraction (Jensen and Jacobson 1962; Gorski et al. 1968). Reports of
analogous presumptive receptors for other steroid hormones were quick to follow.
Thus, steroid receptors were inferred using a standard endocrinological and phar
macological strategy: begin with a known physiological signaling molecule, and
identify in responsive tissues a protein, a putative receptor, that binds the signal
with high affinity and specificity.
viii Foreword
The cloning of the glucocorticoid receptor (Miesfeld et al. 1984), the first mam
malian transcriptional regulatory factor so isolated, led eventually to elucidation of
the largest superfamily of transcriptional regulatory factors (Mangelsdorf et al. 1995).
At present, the bona fide receptors in the IR superfamily--those with known signal
ing ligands ---are outnumbered by the so-called orphan receptors, for which ligands
remain unidentified. In principle, a given orphan might be constitutive, or even
nonfunctional. However, an intriguing pair of evolution-based arguments persuade
me that cognate ligands exist for most or all of the orphans:
First, efficient intercellular communication is essential for all multicellular or
ganisms. Individual highly differentiated cells must be informed of the status of the
whole organism, and multiple cell types must in tum collaborate to produce appro
priate and coordinate physiological effects. Lipophilic small molecules seem ideal
as signals: they are simple to synthesize or acquire from the environment, rela
tively stable in circulation, and may readily enter target cells. Structural simplicity,
however, invokes an "information capacity paradox": how can molecules that lack
chemical complexity symbolize complex physiological states? Receptors resolve
the paradox: their association with a ligand can be viewed as a large-scale "chemi
cal modification" of the ligand, providing it with sufficient complexity to specify
within target cells complex programs of gene expression. This general logic, bind
ing of macromolecular adapters to small molecules as a way to impart complexity,
is not unique in biology. For example, the interaction of a transfer RNA with its
cognate amino acid could be considered as a chemical modification of the amino
acid that confers on that simple molecule sufficient chemical complexity to read the
genetic code (Yamamoto 1985). The point here is that intercellular signals, and
therefore receptors, are essential for all multicellular organisms --- and that com
plex multicellular organisms likely require more signals and more receptors than do
simple organisms .
The second evolution-based observation is that IRs, remarkably, are a new gene
family, found only in metazoans. IR-related genes are not found in fungi or in
higher plants --- the eukaryotes from which the metazoans most recently diverged
---or more distantly related eukaryote, in eubacteria, or in archae. Moreover, the
steroid receptor subfamily of IRs is found only among the most complex meta
zoans, the vertebrates. Finally, the DNA binding and ligand binding domains ap
pear to have evolved as a unit (albeit at different rates, indicating different evolu
tionary pressures on the two domains) (Amero et al. 1992); notably, all orphans
include both domains. Thus, the IRs do not represent an ancient family of regula
tors in which a subset was recently co-opted to mediate signaling by lipophilic
ligands. Rather, it appears that IRs evolved in metazoans specifically to exploit
simple lipophilic molecules for intercellular signaling. Interestingly, recent studies
hint that lipophilic ligands may signal in higher plants through another new gene
family, unrelated to IRs, that is unique to plants (Ulmasov et al. 1997). According
to this line of reasoning, then, each IR will bind to a small metabolite, a nutrient, an
environmental compound, that has acquired a signaling role relatively recently --
after the evolutionary divergence of metazoans, fungi and higher plants.
Foreword ix
These ideas imply that the IRs, and the orphans in particular, could be used as
biological probes to identify cognate ligands and to uncover the "symbolic values"
of those ligands, i.e., the physiological consequences of their signaling. As de
scribed in this volume, this "reverse endocrinology" strategy, in which a cloned
orphan receptor is used to probe for its ligand and biological action, is indeed effec
tive. Perhaps most notably, the investigations described in this monograph, taken
collectively, validate this strategy more broadly, for we learn that it is generally
illuminating to identify, isolate and characterize a broad range of factors that inter
act with IRs, and that in doing so, we learn both about receptor action per se and
about cellular function. Examples of this "receptor as probe" approach are abun
dant and well represented in this volume:
• a multicomponent eukaryotic molecular chaperone complex was shown to
potentiate the ligand responsiveness of IRs and other signaling molecules;
• the first genomic response elements were isolated, revealing a general role for
transcriptional enhancers;
• composite response elements were described, demonstrating a strategy for
producing combinatorial regulation at "nodes" at which different signaling
pathways intersect and communicate;
• IR phosphorylation revealed a separate type of crosstalk node, and showed
that IR activities are determined by integrating multiple signaling inputs;
• specification of receptor oligomerization state ---monomer, homodimer or
heterodimer ---demonstrated another means of combinatorial regulation;
• studies of intracellular trafficking of IRs revealed a class of proteins
that could be targeted to different cellular compartments or
subcompartments, depending on interactions with chaperones, signals and
structural components;
• IR interactions with chromatin remodeling machineries and histone
modification enzymes suggest how regulators contend with chromosome
packaging, and how they may exploit chromatin in regulatory mechanisms;
• the chemical and regulatory subtleties of ligand-receptor interactions are
providing in atomic detail a view of allosteric transitions, and a primary
role for hydrophobic core rearrangements in transmitting those changes;
• the role of IRs in physiology, development and disease has opened a window
on molecular interactions that drive complex phenomena.
From the vantage point of the receptors, many of its molecular interactions can
be considered to be signaling interactions (Yamamoto 1997) that "inform" the re
ceptor both of the state of the cell and of the organism in order to specify the
precise receptor activity appropriate for a given context. Thus, the IR superfamily
functions in metazoans to coordinate a symphony of signals; indeed, the entire
superfamily appears to have co-evolved in metazoans in parallel with a cognate
family of new signals.
Beginning with a bold but unsubstantiated pronouncement over two centuries
ago, it is apparent that signal transduction now holds center stage in studies of
fundamental cellular processes, such as cell division and gene expression, in sweeping
analyses of development and the nervous system, and in discovery of the molecular
x Foreword
the molecular bases of disease. Fittingly, The Molecular Biology of Steroid and
Nuclear Hormone Receptors maps out the present-day position on that stage for a
large and important family of signal integrators and gene regulators, and it does so
through the voices of some of the next generation of leading investigators in that
field.
Keith R. Yamamoto
Department of Cellular and Molecular Pharmacology
University of California
San Francisco, California 94143-0450
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