Molecular Biology and Physiology of Insulin and Insulin-Like Growth Factors

527 Pages·1991·18.417 MB·English

by  J. S. Sussenbach, P. H. Steenbergh, E. Jansen, P. Holthuizen, D. Meinsma (auth.), Mohan K. Raizada, Derek LeRoith (eds.)

MOLECULAR BIOLOGY
AND PHYSIOLOGY OF
INSULIN AND
INSULIN-LIKE GROWTH
FACTORS
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK, State University of New York at Buffalo
IRUN R. COHEN, The Weizmann Institute of Science
DAVID KRITCHEVSKY, Wistar Institute
ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research
ROOOLFO PAOLETTI, University of Milan
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MOLECULAR BIOLOGY
AND PHYSIOLOGY OF
INSULIN AND
INSULIN-LIKE GROWTH
FACTORS
Edited by
Mohan K. Raizada
University of Florida
Gainesville, Florida
and
Derek LeRoith
National Institutes of Health
Bethesda, Maryland
PLENUM PRESS • NEW YORK AND LONDON
Library of Congress C8taloglng-ln-Publlcatlon Data
International Symposi~m on Molecular and Cellular Biology of Insulln
and IGFs (3rd : 1990 : Gainesvllle, Fla.)
Molecular biology and physiology of insulin and insulin-like
growth factors I edited by Mohan K. Raizada and Derek LeRoith.
p. cm. -- (Advances in experImental medicine and biology; v.
293)
"Proceedings of the Third International Symposium on Molecular and
Cellular Biology of Insulin and IGFs, held October 12-14, 1990, in
Gainesville, Florida"--T.p. verso.
Includes bibliographical references and index.
ISBN-13: 978-1-4684-5951-7
1. So.atomedin--Mechanism of action--Congresses. 2. Insulin-like
growth factor-binding protej~s--Congresses. 3. Insulin--Mechanjs~
of action--Congresses. I. Ralzada, Mohan K. II. LeRoith, Derek,
1945- . III. Title. IV. Series.
[DNLM: 1. Central Nervous System--physiology--congresses.
2. Insulin--physiology--congresses. 3. InsulIn-LIke Growth Factor
I--physiology--congresses. 4. InsulIn-Like Growth Factor 11-
-physiology--congresses. 5. Receptors, Insulin--congresses. Wl
AD559 v. 293 I WK 820 1611. 1990]
QP552.S65I58 1991
599' . 031--dc20
DNLM/DLC
for Library of Congress 91-24015
CIP
Proceedings of the Third International Symposium on
Molecular and Cellular Biology of Insulin and IGFs,
held October 12-14, 1990, in Gainesville, Florida
ISBN-13: 978-1-4684-5951-7 e-ISBN-13: 978-1-4684-5949-4
DOl: 10.1007/978-1-4684-5949-4
© 1991 Plenum Press, New York
Softcover reprint ofthe hardcover lst edition 1991
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
PREFACE
This volume addresses a fundamental puzzle in biology and medicine, namely, how does
tissue develop, repair and replace itself. The answer appears to lie in growth factors and their
regulation. To thrive and survive we need growth factors and this book concentrates on two
factors that are related to growth hormone. Growth hormone does not act directly on all
tissues, but mediates many of its actions through the release of insulin-like growth factors
from the liver. The growth factors were originally called somatomedins by McConaghey and
Sledge (1), who discovered that they mediated growth-like effects of growth hormone.
However, the factors were purified on the basis of their insulinomimetic actions on fat and
muscle and it is their relationship to the insulin family of pep tides that now gives them their
name (2,3) of insulin-like growth factors (IGFs). They mediate the actions of. growth hormone
on the proteoglycan synthesis of cartilage and produce mitogenic effects in fibroblast cultures.
It is now recognized that IGF-I and IGF-II have local cellular actions and that they are the
key to many essential functions in the daily routine lives of cells of every tissue. They are
not only factors for linear growth in skeletal tissue, as was first thought, but they also
stimulate DNA synthesis and cause cell division in diverse cell populations, including human
cell lines. One cannot yet make a hard and fast rule about the different actions of IGF-I
compared to IGF-II but we do know they have separate receptors. There is consensus that
both factors are fetal growth promoters and have both short-term metabolic effects and long
term growth effects. In the adult IGF-I is mostly synthesized in the liver and secreted into
the circulation, whereas as IGF-II is synthesized in nonhepatic tissues. It appears that
sustained and balanced growth requires the endocrine and paracrine functions of both factors.
In humans, the importance of IGFs is well illustrated by the finding that pygmies have
a genetic inability to produce IGF-I, particularly at puberty, which results in their shorter
v
stature (4) The lack of IGF-I secretion appears to be due to a GH receptor deficiency. The
human IGF-I and IGF-II gene have been mapped (5,6) but the expression is complex due to
the different stages of development in different tissues. There are promoters for early
development and other promoters for later development. It is this interplay of genetics,
hormone secretion, regulation, and the molecular receptors for the growth factors and insulin
that is the focus of this book. The volume collects together the most recent findings and
insights into the molecular physiology of IGFs. It is a timely harvesting of a rapidly growing'
field of research.
The first section deals with the structural and regulatory aspects of IGFs. This
includes the human genes which encode them, the expression in somatic cell hybrids, and the
application of recombinant EGF-1. The EGFs are characterized by their biological activity
and the complexity of biosynthesis and points at which EGFs can be regulated are discussed.
The molecular biology of the insulin-like growth factors are covered in these chapters, bringing
together the world's most preeminent researchers in growth hormone and growth factor
research.
In the second section, new areas which have blossomed in this field including studies
on insulin-like growth factor binding proteins are reviewed. The IGFs are present in the
serum in other biological fluids and although they are water soluble, they bind to large
proteins. These insulin growth factor binding proteins (IGFBP) are unrelated to be the IGF
receptor proteins. Four IGFBPs have been cloned from human and rat tissues. It appears
likely that more may be discovered in the future. It is still a mystery what functional role
these binding proteins play. They may protect tissue from the insulin activity of the insulin
like peptides or they may enhance the actions of IGFs and their binding ability to receptors.
Whatever role they play, binding proteins are upregulated in the many conditions which cause
growth retardation. The latest data is reviewed in these chapters and the molecular analysis
of the binding proteins are published here for a variety of different tissues, including those
found in the brain ventricles.
Insulin resistance as a clinical entity has stimulated intense interest in insulin and
insulin-like receptors. The importance of receptors for binding to insulin and IGFs is covered
vi
in the third section of this book. Molecular biology has improved the picture that we now
have of membrane receptors and the structural maps of these receptors have been revealed.
Several differences appear between the maps of the insulin, IGF-I and the IGF-II/cation
independent mannose-6-phosphate receptors. Also, the highly relevant glucose transporter gene
family is included in this book. The importance of these receptors to muscle development,
vascular tissue in normal and diabetic states, and during embryogenesis is analyzed by the
chapters in this section.
The final section is devoted to insulin and IGF in the central nervous system. Like
nerve growth factor, IGFs appear to have neurotrophic actions, particularly on cholinergic'
cells. It is suggested that since these cells are impaired in Alzheimer's disease, IGF-I may
have a previously unsuspected role in the disease. IGF-II mRNA is reported to be expressed
on choroid plexus and the leptomeninges of the eNS. IGF-I is expressed in glial and neuronal
cultures. The two components of brain tissue, glia and neurons have proved to be accessible
in cell culture for the study of insulin and IGF receptors and the early response genes, also
known as oncogenes. The early response genes appear to be the key to understanding how
the peptide hormones act, after stimulating the membrane surface receptors and activating
second messengers. Through these genes they influence the promoter sequence of different
genes which lead to the suppression or enhancement of transcription, and thus regulate gene
expression. Both transient and prolonged effects of expression in neurons in glia can be
controlled by the super family of oncogenes. The unfolding picture of IGF action in the
central nervous system is covered in this section and represents the most complete source of
work in this area that is currently available.
For an up-to-date volume covering all the latest developments in insulin-like growth
factors, Mohan K. Raizada and Derek LeRoith have put together this book from the third of
three conferences they have organized in the mild winter climate of Gainesville, Florida. The
first conference in 1987, was on insulin and insulin-like peptides, emphasizing the role of
insulin receptors in the brain (7). The second conference in 19119, was on the molecular and
cellular biology of insulin-like growth factors and their receptors (8) The present book is
based on the 1990 conference. Between each conference more advances have been made and
vii
"Molecular Biology and Physiology 0/ Insulin and Insulin-like Growth Factors", brings insulin
and insulin-like growth factors back together again in a most comprehensive review of their
molecular biology and physiology. As an observer of the field, I am full of admiration for
the achievements of all the authors in this volume and the incredible progress that has been
made in the last few years. This book will be an essential source for physicians, nutritionists,
and scientists, dealing with the molecular and cellular physiology of growth and growth
retardation. This includes a widening circle of clinical states in which EGFs are implicated
Among these are diabetes, renal failure, steroid excess, lung and breast cancer, disorders of
nutrition and metabolism and disturbances of the brain which may be involved in Alzheimer's
disease, Down's syndrome and megalencaphaly.
M. Ian Phillips, D.Sc.
Professor and Chairman
Department of Physiology
University of Florida
REFERENCES
1. McConaghey, P. and Sledge, C.G. Production of sulphation factor by the perfused
liver. Nature 225:1249, 1970.
2. Rinderknecht, R. and Humbel, R.E. The amino acid sequence of human insulin-like
growth factor I and its structural homology to proinsulin. J. Bioi. Chern. 253:2769-
2776, 1978.
3. Rinderknecht, E. and Humbel, R.E. Primary structure of human insulin growth factor
II. FEBS Letter 89:283-286, 1978.
4. Merimee, T.J., Zapf, J. and Froesch, E.R. Insulin-like growth factors in pygmies and
subjects with pygmy tract: Characterization of the metabolic actions of IGF-I and
IGF-II in man. J. Clin. Endocrinol. and Metab. SS:1081-1087, 1982.
5. Jansen, M., Van Schaik, F.M.A., Ricker, A.T., Bullock, B, Woods, K.H., Gabbay, D.E.,
Nussbaum, A.L. Sussenbach, J.S. and Van den Brande, J.L. Sequence of cDNA"R
encoding human insulin-like growth factor I precursor. Nature 306:609-611, 1983.
6. Jansen, M., Van Schaik, F.M.A., Van Tol, H. Van den Brande, J.L. and Sussenbach,
J.S. Nucleotide sequences of cDNAs encoding precursors of human insulin-like growth
factor II (IGF-II) and a variant of IGF-II. FEBS Letter 179:243-246, 1988.
7. Raizada, M., Phillips, M.I. and LeRoith, D. Insulin, insulin-like growth factors and
their receptors in the central nervous system. Plenum Press, New York, NY, 1987.
8. LeRoith, D. and Raizada, M. Molecular and cellular biology of insulin-like growth
factors and their receptors. Plenum Press, New York, 1989.
viii
CONTENTS
SECTION I: INSULIN-LIKE GROWTH FACTORS I AND II
Structural and regulatory aspects of the human genes encoding
IGF-I and -II .............................. .
J. S. Sussenbach, P. H. Steenbergh, E. Jansen, P. Holthuizen,
D. Meinsma, M. A. van Dijk and T. Gloudemans
Structural and functional characterization of IGF-I RNA 3' variants 15
P. Kay Lund, Eileen C. Hoyt and Judson J. Van Wyk
Characterization of the biological activity of IGF I analogs with
reduced affinity for IGF receptors and binding proteins . . . . 23
Margaret A. Cascieri, Gary G. Chicchi and Marvin L. Bayne
Insulin-like growth factor II: Complexity of biosynthesis and
receptor binding ........................ . 31
Steen Gammeltoft, Jan Christiansen, Finn C. Nielsen and
Sten Verland
Development of a specific radioimmuno assay for E domain containing
forms of insulin-like growth factor II ..................... 45
James F. Perdue, Linda K. Gowan, W. Rogbert Hudgins,
Joan Scheuermann, Beverly Foster and Sharon Northcutt Brown
The role of the IGFs in myogenic differentiation . 57
K. A. Magri, D. Z. Ewton and J. R. Fiorini
Extinction of human insulin-like growth factor II expression in somatic
cell hybrids ................................. 77
Raffaele Zarrilli, Vittorio Colantuoni, Raffaella Faraonio,
Stefano Casola, Elena Rossi and Carmelo B. Bruni
The growth hormone-insulin-like growth factor I axis: Studies in man
during growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Thomas J. Merimee, Suzanne Quinn, Betty Russell and
William Riley
ix
Recombinant human insulin-like growth factor I: Effects in normal
subjects and implications for use in patients . . . . . . . . . 97
Hans-Peter Guier, Katharina Wettstein, Werner Schurr,
Jurgen Zapf and E. Rudolf Froesch
Single sc administration of insulin-like growth factor I (IGF-I) in
normal men . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Naomi Hizuka, Kazue Takano, Kumiko Asakawa, Izumi Fukuda,
Izumi Sukegawa, Kazuo Shizume and Hiroshi Demura
SECTION II: INSULIN-LIKE GROWTH FACTOR BINDING PROTEINS
Insulin-like growth factor binding protein control secretion and
mechanisms of action ...................... . 113
David R. Clemmons
Regulation and actions of insulin-like growth factor binding protein-3 . . 1 25
Robert C. Baxter and Janet L. Martin
Regulation of gene expression of rat insulin-like growth factor
binding proteins 1 and 2 .......................... 1 37
Matthew M. Rechler, Alexandra L. Brown, Guck T. Ooi,
Craig C. Orlowski, Lucy Y.- H. Tseng and Yvonne W.-H. Yang
Hormonal regulation of insulin-like growth factor binding protein-1
expression in the rat . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Liam J. Murphy and Jiangming Luo and Charita Seneviratne
Cerebrospinal IGF binding proteins: Isolation and characterization 161
Michel Binoux, Monireh Roghani, Paul Hossenlopp and
Odile Whitechurch
The effect of quantity and nutritional quality of dietary proteins on
plasma concentration of insulin-like growth factor binding proteins
(IGFBP) and the saturability of IGFBP with endogenous IGF-I 171
Hisanori Kato, Tsutomu Umezawa, Yutaka Miura and
Tadashi Noguchi
Presence of insulin-like growth factors and their binding protein in
rat milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 9
Anthony F. Philipps, Jean M. Wilson, Radhakrishna Rao,
David M. McCracken and Otakar Koldovsky
SECTION III: RECEPTORS FOR INSULIN, IGF-I AND II
Molecular heterogeneity of insulin receptors in rat tissues 187
Barry J. Goldstein and Alana L. Dudley
x