Vitamins and Hormones

Visit the link below to download the full version of this book:

https://medipdf.com/product/vitamins-and-hormones-5/

Click Download Now

 Editorial Board

CHYTIL
FRANK
MARYF. DALLMAN
JENNYP. GLUSKER
ANTHONYR. MEANS
BERTW. O’MALLEY
VERNL. SCHRAMM
MICHAEL
SPORN
ARMENH. TASHJIAN,JR.
VITAMINS AND HORMONES
ADVANCES IN RESEARCH AND APPLICATIONS

Editor-in-Chief
GERALDLITWACK
Department of Pharmacology
Jefferson Cancer Institute
Thomas Jefferson University Medical College
Philadelphia, Pennsylvania

Volume 51

ACADEMIC PRESS
San Diego New York Boston
London Sydney Tokyo Toronto
This book is printed on acid-free paper. @

Copyright 0 1995 by ACADEMIC PRESS, INC.

A11 Rights Reserved.

No part of this publication may be reproduced or transmitted in any form or by any
means, electronic or mechanical, including photocopy, recording, or any information
storage and retrieval system, without permission in writing from the publisher.

Academic Press, Inc.

A Division of Harcourt Brace & Company
525 B Street, Suite 1900, San Diego, California 92101-4495

United Kingdom Edition published by

Academic Press Limited
24-28 Oval Road, London NWI 7DX

International Standard Serial Number: 0083-6729

International Standard Book Number: 0- 12-709851-8

PRINTED IN THE UNITED STATES OF AMERICA

95 96 9 7 9 8 99 0 0 Q W 9 8 7 6 5 4 3 2 I
 Former Editors
ROBERTS. HARRIS KENNETH V. THIMANN
Newton, Massachusetts University of California
Santa Cruz, California
JOHNA. LORRAINE IRA G. WOOL
University of Edinburgh
Edinburgh, Scotland University of Chicago
Chicago, Illinois
PAULL. MUNSON EGONDICZFALUSY
University of North Carolina Karolinska Sjukhuset
Chapel Hill, North Carolina
Stockholm, Sweden

JOHNGLOVER ROBERTOLSON
University of Liverpool School of Medicine
Liverpool, England State University of New York
at Stony Brook
GERALD
D. AURBACH Stony Brook, New York
Metabolic Diseases Branch
National Institute of Diabetes DONALDB. MCCORMICK
and Digestive and Kidney Diseases Department of Biochemistry
National Institutes of Health Emory University School of Medicine
Bethesda, Maryland Atlanta, Georgia
This Page Intentionally Left Blank
 Contents

.................................................................
PREFACE xi

CAMP-Dependent Regulation of Gene Transcription

by cAMP Response Element-Binding Protein
and cAMP Response Element Modulator
JOEL
F. HABENER,
CHRISTOPHER
P. MILLER,AND MARIOVALLEJO
I.Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
11.CAMP-Dependent Signal Transduction Pathway 2
111.CAMP-ResponsiveTranscription Factors CREB, 6
IV. CAMP Response Elements ..................... . . . . . . . . . . . . . . . . . . . . . 8
V. Mechanisms of Transciptional Transactivation . . . . . . . . . . . . . . . . . . . . . . . 12
VI. The CREB and CREM Genes Are Multiexonic in Structure:
Alternative Exon Splicing Generates a Complex Array of Isoproteins
That Are Either Transactivators or Transrepressors . . . . . . . . . . . . . . . . . . 21
VII. CAMP-Dependent Autoregulation of the Expression of the CREB and
CREM Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
VIII. Roles of CREB and CREM in the Physiological Regulation of Gene
.......................................... 32
IX. on Network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
X. Oncogenic Forms of CREB, CREM, and ATF-1 . . . . . . . . . . . . . . . . . . . . . . . 42
XI. Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
References .................................................. 46

Multiple Facets of the Modulation of Growth by cAMP

PIERRE
P. ROGER, SYLVIA
REUSE,CARINEMAENHAUT,
AND JACQUES
E. DUMONT
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
11. Negative Control of Cell Cycle Progression by cAMP . . . . . . . . . . . . . . . . . 73
111. Positive Control of Cell Cycle Progression by cAMP . . . . . . . . . . . . . . . . . . 83
IV. Relationship between Growth and Differentiation Controls by cAMP . . 118

vii
 ...
Vlll CONTENTS

V. A Role for Cytoskeleton Changes in Control of Growth by CAMP? . . . . . 122

VI . CAMP and the Growth of Cancer Cells .............................. 127
VII . Conclusions and Perspectives ....................................... 140
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

Regulation of G-Protein-Coupled Receptors

by Receptor Kinases and Arrestins
L . BENOVIC
AND JEFFREY
RACHELSTERNE-MARR
I . Introduction .... ................... 193
I1. GRK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
I11. Arrestins ........... 213
........... 226
............. 227

Vasopressin and Oxytocin: Molecular Biology and Evolution of the

Peptide Hormones and Their Receptors
EVITAMOHR.WOLFGANG
MEYERHOF.
AND DIETMAR
RICHTER
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
I1. VP and OT Gene Expression and Regulation . . . . . . ............... 237
I11. VP and OT mRNA in Dendrites and Axons . . . . . . . ............... 242
IV. Somatic Recombination between the VP and OT Genes in
Hypothalamic Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
V. Evolution of the Vertebrate VP/OT Gene Family ..................... 249
VI . Nonapeptide Receptors ............................... 251
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

Structure and Functions of Steroid Receptors

M. G. PARKER
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
I1. Physiological Responses to Estrogens ................................ 268
I11. Intracellular Localization of Estrogen Receptors ..................... 272
IV. Hormone Binding and Receptor Dimerization ........................ 272
V. Target Gene Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
VI . Transcriptional Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
 CONTENTS ix

VII. Specific Gene Transcription by the Estrogen Receptor . . . . . . . . . . . . . . . . 276

VIII. Mechanism of Antiestrogen Action .................................. 277
IX. Cross-coupling with Other Signaling Pathways ...................... 280
References ........................................................ 282

Phosphorylation and Steroid Hormone Action

WENLONG L. WEIGEL
BAIAND NANCY
I. Introduction ....................................................... 289
11. Phosphorylation of Steroid Hormone Receptors ...................... 290
111. Regulation of Steroid Hormone Receptors by Phosphorylation . . . . . . . . . 296
IV. Interaction between Steroid Hormone Action and Signal Transduction
Pathways ......................................................... 301
V. Summary: A Model of Steroid Hormone Action ...................... 305
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

Nucleocytoplasmic Shuttling of Steroid Receptors

ANURADHA
B. DEFRANCO,
DONALD P. MADAN, YUTING TANG,
UMAR. CHANDRAN, XIAO,AND JUNYANC
NIANXING
I. Introduction ....................................................... 315
11. Subcellular Localization of Steroid Receptors ........................ 316
111. Nucleocytoplasmic Shuttling of Steroid Receptors .................... 323
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

'Transcriptional Regulation of the Genes Encoding

the Cytochrome P-450 Steroid Hydroxylases
KEITH L. PARKER P. SCHIMMER
AND BERNARD

I. Introduction . . . . . . ..................................... 339

11. Overview of Steroid
111. Cell-Selective Expression . . . . . . . . . . . . . . . . . . . . . . . . . .
IV. Hormone-Regulated Expression . . . . ..................... 355
V. Perspectives and Future Directio
VI. Summary ............................ .......... 362
References ....................................... 363
X CONTENTS

Stress and the Brain: A Paradoxical Role for Adrenal Steroids

BRUCES. MCEWEN,DAVIDALBECK,HEATHER CAMERON,
HELENM. CHAO,ELIZABETH GOULD,NICOLASHASTINGS,
YASUKAZU KURODA,
VICTORIALUINE,ANAMARIAMAGARINOS,
CHRISTINAR. MCKITTRICK,
MILESORCHINIK, PAVLIDES,
CONSTATINE
PAUL VAHER,YOSHIFUMI WATANABE,AND NANCY
WEILAND
I. Introduction ....................................................... 371
11. Adrenal Steroids and Hippocampal Neuronal Atrophy 374
111. 377
IV. 380
V.
387
VI. 388
VII. Stress Effects on Cognitive Perfo 391
VIII. Deregulation of the HPA Axis in 393
IX. Effects of Exogenous Glucocorticoid Treatment on Cognitive
Performance in Humans ........................................... 394
X. ..................................... 395
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

Retinoids and Mouse Embryonic Development

T. MICHAELUNDERHILL,
LORIE. KOTCH,AND ELWOOD
LINNEY

INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
 Preface

The contents of Volume 51 are divided into two sections. The first
covers cyclic AMP, kinases, and polypeptide hormones and the second
part covers steroid hormone receptors, related genes, and members of
the gene family.
The volume starts with a n in-depth summary of cyclic AMP regula-
tion of gene transcription by CREB and CREM from members of the
laboratory of J. F. Habener. This is followed by a lengthy discussion of
the effects of cyclic AMP on growth by members of the J. E. Dumont
laboratory. Next, a discussion of the G-protein-coupled receptors and
their regulation by kinases and arrestins by R. Sterne-Marr and J. L.
Benovic. The first section is completed by a contribution on the struc-
tural biology and evolution of vasopressin and oxytocin from D. Rich-
ter’s laboratory.
The s e c d section begins with a summary of the structure and
function of steroid receptors by M. G. Parker and is followed by a
discussion on phosphorylation and steroid hormone action from W. Bai
and N. L. Weigel. Next is a work on the nucleocytoplasmic shuttling of
steroid receptors from the D. B. DeFranco laboratory. There is a report
on the transcriptional regulation of genes encoding cytochrome P450
steroid hydroxylases by K. L. Parker and B. P. Schimmer and this is
followed by coverage of adrenal steroid action on stress and the brain
from the B. S. McEwen laboratory. This section ends with a summary
of retinoids and their role in mouse development by the E. Linney
laboratory.
This is a rather large volume and should provide a great deal of up-
to-date information for the researcher and student on several topics of
current interest.
I thank members of the Editorial Board for suggesting some of these
topics and authors. Academic Press continues to be supportive and
prompt in the publication of assembled volumes. I trust that this
fourth volume completed under my guidance will set the tone for fu-
ture numbers in this serial.
GERALD LITWACK

xi
This Page Intentionally Left Blank
 VITAMINS AND HORMONES, VOL. 51

CAMP-Dependent Regulation of Gene Transcription by

CAMPResponse Element-Binding Protein and CAMP
Response Element Modulator
JOEL F. HABENER," CHRISTOPHER P. MILLER,*?'
AND MARIO VALLEJOt
"Laboratory of Molecular Endocrinology
Massachusetts General Hospital
Howard Hughes Medical Institute
Harvard Medical School
Boston, Massachusetts 02114
'Reproductive Endocrinology Unit
Massachusetts General Hospital
Boston. Massachusetts 02114

I. Introduction
11. CAMP-Dependent Signal Transduction Pathway
111. CAMP-Responsive Transcription Factors CREB, CREM, and ATF-1
IV. CAMPResponse Elements
V. Mechanisms of Transcriptional Transactivation
A. Kinases
B. Phosphatases
C. Other Transactivational Domains of CREB
D. Adapter Proteins That Couple CREB Transactivation to the Basal
Polymerase I1 Transcriptional Complex
VI. The CREB and CREM Genes Are Multiexonic in Structure: Alternative Exon
Splicing Generates a Complex Array of Isoproteins That Are Either
Transactivators or Transrepressors
A. Exons Encode Functionally Distinct Domains
B. Repressor Isoforms of CREM Are Generated by Several Different
Mechanisms
C. Alternati.ve Exon Splicing Appears to Provide a Mechanism by Which to
Modulate the Transactivational Activities of CREB and CREM
D. Unphosphorylated CREB Can Repress Gene Expression Mediated by
Phosphorylated CREB
E. Exon-Deleted Repressor Isoform of CREM Down-regulates Expression of the
c-ros and c-iun Genes
VII. CAMP-Dependent Autoregulation of the Expression of the CREB and CREM
Genes
VIII. Roles of CREB and CREM in the Physiological Regulation of Gene
Transcription
A. Testes
B. Anterior Pituitary Gland
C. Brain: Hypothalamus and Pineal Gland
D. Possible Role of CREB in Memory

'Present address: Genetics Institute, Inc., Cambridge, Massachusetts 02140

1 Copyright 1 ) 1995 by Academic Press. Inc
All rights of' reproduction in any form reserved
2 JOEL F. HABENER et al.

IX. CREB/CREM Autoregulation Network

X. Oncogenic Forms of CREB, CREM, and ATF-1
XI. Future Directions
References

I. INTRODUCTION

Forty years have elapsed since the initial discovery of CAMP, the
important second messenger and mediator of cellular signal transduc-
tion (reviewed by Sutherland, 1972). Subsequently followed the discov-
eries of the cellular receptors that serve as sensors of hormones and
other extracellular signaling molecules, the transducers consisting of
stimulatory GTP-binding proteins (Gilman, 19891, and the effector
protein kinases activated by CAMP(Krebs, 1989) involved in the signal
transduction cascade ultimately leading to the regulation of gene ex-
pression. It has been only during the past 7 years that the final media-
tors in the CAMP-dependent signaling cascade have been identified.
These are the CAMP-responsive transcription factors, DNA-binding
proteins whose functions are to stimulate or repress the transcription
of target genes. At least three CAMP-response DNA-binding proteins
have been clearly identified so far: CREB (CAMPresponse element-
binding protein), CREM (CAMP-response element modulator), and
ATF-1 (activating transcription factor 1).
The intent of this chapter is to describe selected aspects of our cur-
rent understanding about the workings of these CAMP-responsive
transcription factors, with the main emphasis on CREB and CREM.
Additional perspectives on CREB and CREM are given in other publi-
cations (Roesler et al., 1988; Habener, 1990; Montminy etal., 1990; Mey-
er and Habener, 1992,1993; Hoeffler, 1992; Foulkes and Sassone-Corsi,
1992; DeGroot and Sassone-Corsi, 1993; Vallejo and Habener, 1994;
Sassone-Corsi, 1994; Lalli and Sassone-Corsi, 1994; Vallejo et al., 1995).

SIGNAL
11. CAMP-DEPENDENT PATHWAY
TRANSDUCTION

In almost all living organisms cells communicate by sending and

receiving chemical signals in the form of neurotransmitters and hor-
mones. These signals induce specific cellular responses, for example,
changes in plasma membrane properties (ion channels or receptors),
cellular growth and metabolism, or gene expression, depending on the
nature of the signal and the specific cell type involved (Herschman,
 CREB AND CREM REGULATION 3

1989; Karin, 1992).To elicit their actions, the signal neurotransmitter

and hormone molecules must first bind to specific high-affinity cellu-
lar receptors that reside in the cytoplasm (e.g., steroid hormone recep-
tors), in the nucleus (e.g., thyroid hormone and retinoid receptors), or
on the cell surface (e.g., plasma hormone receptors) of target cells.
Small lipophilic molecules such as steroid hormones, thyroid hor-
mones, and retinoids can readily diffuse across plasma membranes.
After gaining access to the interior of the cells, these hormones bind to
and activate nuclear or cytoplasmic receptors (Fuller, 1991; Grone-
meyer, 1992; Simons et al., 1992; O’Malley, 1990; Beato, 1989). Often,
the ligand-bound activated receptors are sequence-specific DNA-
binding proteins that regulate the transcription of specific sets of tar-
get genes. Larger and more complex ligands such as peptide hormones
cannot diffuse across plasma membranes. These molecules bind to and
activate receptors located on the plasma membranes of target cells
(Dohlman et al., 1991).The activated cell surface receptors then trans-
duce signals to the interior of the cell by mechanisms that involve
coupling to guanine nucleotide-binding proteins (G proteins) and/or
phosphorylation cascades (Gilman, 1987; Dohlman et al., 1991; Simon
et al., 1991; Yarden and Ullrich, 1988; Ullrich and Schlessinger, 1990).
In many cases these signal transduction pathways lead to the nu-
cleus in order to regulate gene transcription. There are several well-
characterized pathways by which signals can be transmitted from the
cell surface to the nucleus (Fig. 1). These pathways can be concep-
tualized as having four components, or “messenger systems.” The first
messenger is the hormone ligand, a macromolecule that binds to the
cell surface receptor coupled to the G proteins. This complex is respon-
sible for sensing the signal (receptor) and transmitting the signal (G
protein) across the plasma membrane. The first messenger systems
regulate intracellular levels of second messengers such as CAMP,di-
acylglycerol, and calcium (Ca2+).These regulatory substances are re-
sponsible for the transfer of information from the interior of the
plasma membrane throughout the cell. The second messengers regu-
late the activities of the third component, effector molecules such as
CAMP-dependentprotein kinase A (PKA),protein kinase C (PKC), and
calmodulin-dependent protein kinase (CaMK).These kinases regulate
by phosphorylations the activities of the final component in the signal
transduction pathways, DNA-binding proteins such as CREB. CREB is
one of several closely related transcription factors capable of mediat-
ing transcriptional regulation by cAMP (see below).
The cAMP signaling pathway is one of the most important intra-
cellular signal transduction pathways in eukaryotic cells (Habener,
4 JOEL F. HABENER et al

CAMP- PKA RIPTION

FIG.1. The cellular signal transduction pathways that modulate gene transcription.
The steps in the signaling pathways are designated as first through fourth component
messengers (see text). The first components are hormones and ligands (H,, H,, and H,)
that bind to and activate cell surface receptors (Rl, R,, and R3), leading to elevation of
intracellular levels of second messenger mediator molecules and subsequent activation
of effector proteins (third messengers). The effector proteins are typically kinases that
phosphorylate the fourth messengers, DNA-binding proteins. The DNA-binding phos-
phoprotein CREB is activated by the cAMP signaling pathway. DAG, diacylglycerol;
PKC, protein kinase C; PKA, protein kinase A; CaMK, calmodulin-dependent protein
kinase; P, phosphate.

1993) (Fig. 2). Elevation of intracellular cAMP occurs when plasma

membrane receptors coupled to stimulatory G proteins (G,) are bound
and activated by their specific ligands, leading to the activation of
adenylyl cyclase (AC). AC catalyzes the conversion of ATP to CAMP,
which then binds and activates PKA. In the absence of CAMP, the
inactive PKA holoenzyme is a heterotetrameric protein complex con-
sisting of two regulatory subunits (R) and two catalytic subunits (C).
Thus far, two classes of R subunits (RI and RII), each with two isoforms
(RIa, RIP, RIIa, and RIIP), and three isoforms of the C subunit (Ca,CP,
and Cr) have been described. cAMP binds cooperatively to two sites on
the R subunits within the holoenzyme, thereby liberating free active C
subunits. In addition to modulating the activity of the C subunits, the
RII subunits bind proteins known as A kinase-anchoring proteins
(AKAPs). AKAPs are a family of proteins responsible for tethering
type I1 PKA holoenzyme to specific cellular structures, including the
nuclear matrix (Scott and McCartney, 1994).Recent experimental evi-
dence indicating the presence of PKA holoenzyme within the nucleus
is described later (Section V1,D). Nuclear compartmentalization of
type I1 PKA may play a n important role in regulating the phospho-
rylation of nuclear proteins. It appears that the transactivational ac-
 CREB AND CREM REGULATION 5

mRNA
t
Protein

FIG.2. CREB-mediated CAMP-dependent gene transcription. Hormones and ligands

(H) that bind plasma membrane receptors coupled to stimulatory GTP-binding proteins
(G,) induce an increase in intracellular cAMP levels by activation of adenylate cyclase
(Ac), which then catalyze the conversion of ATP to CAMP. Increases in cAMP levels
cause dissociation of protein kinase A (PKA) holoenzyme to liberate inactive regulatory
subunits (R)and active catalytic subunits (C); the latter are translocated to the nucleus to
phosphorylate (P+)transcription factors such as CREB. Nuclear translocation of PKA C
subunits is regulated, whereas translocation of CREB is constitutive. CREB binds to
cAMP response elements (CREs; e.g., 5'-TGACGTCA-3'), leading to increased gene tran-
scription and subsequent protein synthesis. R, receptor and regulatory subunit of PKA.

tivity of CREB may be regulated, in part, at the level of the reversible

translocation of the free active catalytic subunit of PKA from the cyto-
plasm to the nucleus (Hagiwara et al., 1993). CREB itself is constitu-
tively transported into the nucleus, where it awaits phosphorylation.
This situation is different from that of several other transcription fac-
tors, such as the thyroid hormone T, and glucocorticoid receptors, Nu-
clear factor-&, and CAAT box/enhancer-binding protein p (C/EBP-p).
The transport of these proteins from the cytoplasm to the nucleus is
activated by phosphorylation, although the exact mechanisms for this
regulation are not fully understood.
CREB contains a strong consensus site (RRPSY) for phosphorylation
by PKA. This site lies within a portion of CREB known as the phospho-
rylation region (P box), or kinase-inducible domain (KID). Phospho-
rylation of the serine residue within this sequence potently activates
the transactivation functions of CREB (Gonzalez and Montminy,
1989). Within the nucleus CREB recognizes and binds to DNA se-
quences typified by the consensus palindromic cAMP response ele-
ment (CRE), 5'-TGACGTCA-3' (Section IV).