Molecular Biology of Brain and Endocrine Peptidergic Systems

317 Pages·1988·12.016 MB·English

by  Joel F. Habener, Paul J. Deutsch, James P. Hoeffler, J. Larry Jameson (auth.), Michel Chrétien, Kenneth W. McKerns (eds.)

Molecular Biology of
Brain and Endocrine
Peptidergic Systems
mOCHEMICALENDOCmNOLOGY
w.
Series Editor: Kenneth McKerns
HORMONAL CONTROL OF THE HYPOTHALAMO-PITUITARY
GONADAL AXIS
Edited by Kenneth W. McKerns and Zvi Naor
HORMONALLY ACTIVE BRAIN PEPTIDES: Structure and Function
Edited by Kenneth W. McKerns and Vladimir Pantie
MOLECULAR BIOLOGY OF BRAIN AND ENDOCRINE PEPTIDERGIC SYSTEMS
Edited by Michel Chretien and Kenneth W. McKerns
NEUROENDOCRINE CORRELATES OF STRESS
Edited by Kenneth W. McKerns and Vladimir Pantie
NEUROENDOCRINE MOLECULAR BIOLOGY
Edited 12y G. Fink, A. J. Harmar, and Kenneth W. McKerns
REGULATION OF GENE EXPRESSION BY HORMONES
Edited by Kenneth W. McKerns
REGULATION OF TARGET CELL RESPONSIVENESS, Volumes 1 and 2
Edited by Kenneth W. McKerns, AsbjC1Srn Aakvaag, and Vidar Hansson
REPRODUCTIVE PROCESSES AND CONTRACEPTION
Edited by Kenneth W. McKerns
STRUCTURE AND FUNCTION OF THE GONADOTROPINS
Edited by Kenneth W. McKerns
SYNTHESIS AND RELEASE OF ADENOHYPOPHYSEAL HORMONES
Edited by Marian Jutisz and Kenneth W. McKerns
Molecular Biology of
Brain and Endocrine
Peptidergic Systems
Edited by
Michel Chretien
Clinical Research Institute
Montreal, Quebec, Canada
and
Kenneth W. McKerns
International Foundation for Biochemical Endocrinology
Blue Hill Falls, Maine
PLENUM PRESS •
NEW YORK AND LONDON
Library of Congress Cataloging in Publication Data
Molecular biology of brain and endocrine peptidergic systems I edited by Michel
Chretien and Kenneth W. McKerns.
p. cm. - (Biochemical endocrinology)
Proceedings of a symposium held Oct. 13-16, 1987 in Montreal, Quebec, Canada
under the auspices of the Canadian -Biochemical Society and the International Founda
tion for Biochemical Endocrinology.
Includes bibliographies and index.
ISBN 978-1-4684-8803-6 ISBN 978-1-4684-8801-2 (eBook)
DOI 10.1007/978-1-4684-8801-2
I. Brain chemistry-Congresses. 2. Molecular neurobiology-Congresses. 3. Neuro
peptides-Congresses. 4. Neuroendocrinology-Congresses. 5. Canadian Biochemical
Society. I. Chretien, Michel, 1936- . II. McKerns, Kenneth W. III. International
Foundation for Biochemical Endocrinology. IV. Series.
[DNLM: I. Neurobiology-congresses. 2. Neuroendocrinology-congresses. 3.
Neuropeptides - congresses. WL 300 M717 5 1987]
QP376.M587 1988
599'.0188-dcl9
DNLM/DLC 88-12958
for Library of Congress CIP
Proceedings of a symposium on Molecular Biology of Brain and
Endocrine Peptidergic Systems, held October 13-16, 1987,
in Montreal, Quebec, Canada
© 1988 Plenum Press, New York
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
Softcover reprint of the hardcover I st edition 1988
All righ ts 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
We had the pleasure and the great opportunity to organize a symposium
on "Molecular Biology of Brain and Endocrine Peptidergic Systems" under
the auspices of the Canadian Biochemical society and the International
Foundation for Biochemical Endocrinology. We were indeed very happy to
ass~ble a series of first rate speakers who delivered excellent papers on
a variety of subjects from the synthesis of complicated peptide analogs,
to the creation of trangenic mice, site-directed mutagenesis, enzyme
characterization and DNA binding sites. One hundred and seventy-five
participants attended the 40 conferences while having the opportunity to
look at 24 posters presented by senior scientists as well as students.
We, of the organizing committee, feel extremely pleased to have received
an overwhelming response from such a group of scholars. We wish to
express our sincere gratitude to Mrs. Diane Marcil who arranged most
aspects of the meeting with efficiency. We also thank the different
organizations and companies for their generous grants which made
the reunion possible.
We hope that the participants have gained scientifically while having
a pleasant sojourn in beautiful Montreal. The organizing committee was
made up of a group of dedicated people, particularly its secretary,
Dr. Philippe Crine. To all speakers and sessions chairpersons, we are
indebted for the excellence of their participation.
Joseph Martin delivered the opening ceremonies and P.W. Choppin was
the key-note speaker at the banquet. The scientific sessions were chaired
by Michel Chretien, Claude Lazure, Paul Brazeau, Guy Boileau, Andre
DeLean, Paul Cohen, Remi Quirion, Christina Gianoulakis and Mona Nemer.
Michel Chretien
Kenneth W. McKerns
v
ACKNOWLEDGMENTS
The Editors wish to thank the members of the committees for their
remarkable efforts in arranging a marvelous meeting:
Malur R. Sairam, Peter W. Schiller, Nabil G. Seidah, Guy Boileau, Paul
Brazeau, Jacques Drouin, Claude Lazure Philippe Crine and Majambu
Mbikay and the Executive Assistant Diane Marcil.
We wish to acknowledge with thanks
Le Fonds de la Recherche en Sante du Quebec (FRSQ)
Dr. Yvon Gauthier, Dean, Faculty of Medicine, University of Montreal
The Medical Research Council of Canada
The National Research Council and Dr. Bernard Coupal
and
Bristol-Myers Pharmaceutical Group
Ciba-Geigy Canada Ltd.
Merck Frosst Canada Inc.
Nordic Laboratories Inc.
Pfizer Canada Inc.
Rhone-Poulenc Pharma Inc.
Sandoz Canada Inc.
Squibb Canada Inc.
vii
CONTENTS
GENErIC ENGINEERING OF POLYPEPTIDE HORM:lNES (MUTAGENESIS)
Functional Dissection of a cAMP-Response Element Using . . .
Recombinant Mutations • • • • • • • • • • • • • • 1
J.F. Habener, P.J. Deutsch, J.P. Hoeffler and J.L. Jameson
STRUCTURE ACTIVITY RElATIONSHIP AND PEPTIDE DRUG DESIGN
Conformational Constraints in the Design of Receptor Selective
Peptides: Conformational Analysis and Molecular Dynamics. 13
V.J. Hruby, W. Kazmierski, B.M. Pettitt and F. Al-Obeidi
Angiotensin II Antagonists with Prolonged Duration of Action,
Possible Anti-Hypertensive Drugs. • • • • • • • • • • • • 29
E. Escher
New Concepts in Peptide Analog Design. 47
P. W. Schiller
CLINICAL AND EXPERIMENTAL APPLICATIONS OF POLYPEPTIDE HORM:lNES
Neuropeptidergic Pathways as Possible Targets for the Development
of New Therapeutic Agents • • • . . • • . • • • • • • • • •• 63
B.P. Roques
Combination Therapy with the Antiandrogen Flutamide and the LHRH
Agonist [D_Trp ,des-Gly-NH;o ]LHRH Ethylamide in Prostate
6
Cancer: Rationale and 5-year Clinical Experience. • • 83
F. Labrie, A. Dupont, A. Belanger, J. Simard, C. Labrie,
R. Poulin, I.Luthy, R. Veilleux, D. Lacoste, B. Marchetti,
L. Cusan, G. Manhes, G. Monfette and J. Emond
ORGANELLE ORGANIZATION AND INTRACELLUlAR TRAFFICKING
. . . . . . . . . . . . . . . . . .
Proinsulin Conversion Site 103
L. Orci
ix
HORmNE AND RECEPIOR LIGAND INI'ERAcrIONS
Regulation of the Adenylate Cyclase Signalling Pathway: Potential
Role for the Phosphorylation of the Catalytic Unit By
Protein Kinase A and Protein Kinase C • • • • • • • • • • • •• 123
T. Yoshimasa, M. Bouvier, J.L. Benovic, N. Amalaiky,
Robert J. Lefkowitz and M.G. Caron
Role of Glycosylation in Ligand-Receptor Interactions and Signal
Transduction Mechanisms • • • • • • • • • • • • • • • • • • 141
M.R. Sairam
POST-TRANSLATIONAL PROCESSING OF PEPTIDE HORmNES
Molecular Structure of Neutral Endopeptidase 24.11
(Enkephalinase) • • • • • • • • • ,. • • • • • • • • • • • 159
P. Crine, G. Boileau, A. Devault, M. Zollinger and M. Aubry
The Possible Role of Plasma Kallikrein in Pro-Hormone and
Pro-Enzyme Processing. • • • • • • • • • • • • 179
N.G. Seidah, J. Paquin, J. Hamelin, K. Metters, S. Benjannet,
M. Mbikay, C. Lazure and M. Chretien
Sequence Analysis of the Carboxypeptidase E Precursor. • • • • • 189
L.D. Fricker
Cellular Mechanisms of Peptide Processing: Focus on a-Amidation. 201
R.E. Mains, V. May, E.I. Cullen and B.A. Eipper
The Yeast KEXl Gene Product Acts as a Carboxypeptidase B-Like
Protease in Processing Secreted Protein Precursors. • •• 215
A. Cooper and H. Bussey
RECEPIOR LOCALIZATION AND IN SITU HYBRIDIZATION
Regulation of mRNA in Peptidergic Systems: Quantitative
and In Situ Studies • • • • • • • • • • • • • • • 225
S. J. Watson, T.G. Sherman, M.K. Schafer, P. Patel,
J. P. Herman and H. Akil
Cellular and Sub-Cellular Localization of Brain Neurotensin
Receptors ••••••••••••••••••••••• 243
A. Beaudet, E. Szigethy, J.P. Kessler, C. Dana, J. Mazella
and E. Moyse
GONAOO'IROPINS AND NOVEL GONADAL PEPTIDES.
ISOLATION, S'IRUcruRE AND CLONING
Diversity of Novel Proteins of Gonadal Fluids. • • • • • • 259
r.
Manjunath, L. Baillargeon, Y.L. Marcel, N.G. Seidah,
M. Chretien and A. Chapdelaine
Biochemical and Biological Characterization of LH and FSH
Expressed by Recombinant DNA Technology • • • • • • • 275
S. C. Chappel
x
REGUlATION OF NEUROPEPITDE GENE EXPRESSION
DNA Binding Proteins and Their Roles in Controlling Tissue
Specific Gene Expression and the Responses to Second
t-1es sengers • • • • • • • • • • • • • • • • • • • • • • 289
M. Karin, M. Bodner, R. Chiu, P. Angel, D. Wu, S. Dana,
E. Satuloff and M. Imagawa
Molecular Biology and Physiology of Aplysia Neuropeptides. 299
L. DesGroseillers and R.H. SCheller
Index • . • • • . • . • . • . . . . • • • • • • • . • • . . . •• 315
xi
FUNCTIONAL DISSECTION OF A cAMP-RESPONSE
ELEMENT USING RECOMBINANT MUTATIONS
Joel F. Habener, Paul J. Deutsch, James P. Hoeffler
and J. Larry Jameson
Laboratory of Molecular Endocrinology
Massachusetts General Hospital
and Howard Hughes Medical Institute
Harvard Medical School, Boston, MA02114
Summary
The human CG-a gene expressed in the placenta is transcriptionally activated by
cAMP. Two copies of a palindrome, 5'-TGACGTCA-3', similar to sequences in other
cAMP-responsive genes, reside within two identical 18-bp sequences arranged as
adjacent direct repeats in the CG-a S'-flanking region. DNase footprint and gel
mobility shift analyses identify interactions of binding proteins with the 18-bp
repeats at -146 to -111, with a more upstream expression sequence (UES) at -178 to -
156, and with a more downstream sequence, including a CCAAT-box-Iike element (DES)
at -100 to -72. One or two synthetic copies of the 18-bp sequence fused to the CG-a
promoter enhance transcription of a reporter chloramphenicol acetyl transferase
(CAT) gene in placental choriocarcinoma (JEG-3) cells when inserted in either
orientation, both 5' to the cap site or 3' of the coding sequence. When paired with
the CGa promoter the 18-bp enhancer exhibits strong preference for JEG-3 cells.
Transcription of fusion genes containing the 18-bp enhancer is stimulated 30- to 40-
fold by 8-br-cAMP, indicating that the 18-bp enhancer is a cAMP-responsive enhancer
(CRE). A single CRE stimulates transcriptional activity 10-fold less than the
double CRE and 100-fold less than the double CRE fused to the UES; the
transcriptional enhancement of the two CREs and the UES are synergistic and not
additive. Synthetic oligonucleotide expression cassettes encompassing the single
CRE, double CRE and UES sequences were used to assess the effects of mutations on
the individual functional elements. Mutations of sequences adjacent to, us well as
point substitutions and deletional mutations within the CRE indicate that the
octamer motif is essential for expression and cAMP responsivity but that synergistic
transcriptional responses are highly dependent upon the surrounding contextual
sequences. Co-transfection and expression of a-gene CAT reporters with increasing
amounts of specific competitor DNA sequences localize the interaction of rate-
limiting stimulatory transacting factors predominantly to the region containing the
CREs and UES (-236 to -100). Saturation expression and competitive inhibition of
expression were indistinguishable in the presence and absence of 8-br-cAMP,
suggesting that the cAMP-mediated enhancement of transcription does not alter
affinities of the binding of factors to the DNA but rather increases the efficiency
of transcription. These studies indicate that the cooperative cis-trans interaction
of cAMP-responsive enhancer-like elements with the homologous promoter and an
upstream element in a constrained cis-context mediated by transacting DNA binding
of
proteins, represents part the mechanism of cell-specific expression of the CG-a
gene.