Boshart, Michael

Dumont, J. E.

Nitsch, Doris

Nunez, J.

Schmidt, Andrea

Schütz, Günther

Weih, Falk

English

Open Access LMU

Hormones and Cell Regulation (n° 14) i i ^ r ^ ^ m e i y et Regu la t ion CelJulaire (n° 14) Colloques INSERM I S S N 0768-3154 Other C o l l o q u e s published as co-editions by John Libbey Eurotext and I N S E R M 133 Cardiovascular and Respiratory Physiology i n the Fetus and Neonate. P h y s i o l o g i e C a r d i o v a s c u l a i r e et R e s p i r a t o i r e du Foetus et du N o u v e a u - n e . Scientific Committee : P. Karlberg, A. Minkowski , W. Oh and L. Stern; Managing Editor : M . Monset-Couchard. I S B N : John Libbey Eurotext 0 86196 125 0 I N S E R M 2 85598 340 1 134 Porphyrins and Porphyrias. Porphyrines et P o r -phyries. Edited by Y. Nordmann. I S B N : John Libbey Eurotext 0 86196 087 4 I N S E R M 2 85598 281 2 137 Neo-Adjuvant Chemotherapy. C h i m i o t h e r a p i e N e o - A d j u v a n t e . Edited by C. Jacquillat, M . Wei l and D. Khayat. I S B N : John Libbey Eurotext 0 86196 125 0 I N S E R M 2 85598 340 1 139 Hormones and Cell Regulation (lOth European Symposium). H o r m o n e s et R e g u l a t i o n C e l l u l a i r e ( 1 0 e Symposium E u r o p e e n ) . Edited by J . Nunez, J . E . Dumont and R. J . B . K ing . I S B N : John Libbey Eurotext 0 86196 125 0X I N S E R M 2 85598 340 1 147 Modern Trends in Aging Research. N o u v e l l e s Perspectives de la R e c h e r c h e sur le V i e i l l i s s e m e n t . Edited by Y. Courtois, B. Faucheux, B . Forette, D.L. Knook and J .A . Treton. I S B N : John Libbey Eurotext 0 86196 126 0X I N S E R M 2 85598 340 1 149 B ind ing Proteins of Steroid Hormones. P r o t e i n e s de Raison des H o r m o n e s S t e r o i d e s . Edited by M.G . Forest and M . Pugeat. I S B N : John Libbey Eurotext 0 86196 125 0 I N S E R M 2 85598 340 IX 151 Control and Management of Parturi t ion. L a M a i t r i s e de la P a r t u r i t i o n . Edited by C. Sureau, P. Blot, D. Cabrol, F. Cavaille and G. Germain. I S B N : John Libbey Eurotext 0 86196 125 0 I N S E R M 2 85598 340 1 II Suite pagel23 Hormones and Cell Regulation Hormones et Regulation Cellulaire Proceedings of the 14th INSERM European Symposium on Hormones and Cell Regulation, held at Mont Sainte-Odile (France), September 25-28,1989 Sponsored by the Institut National de la Santo et de la Recherche Medicale (INSERM) Edited by J . Nunez J . E . Dumont LES EDITIONS Q Q I N S E R M ö ö British Library Cataloguing in Publication Data INSERM European Symposium on Hormones and Cell Regulation { 1 4 t h , 1989, S a i n t e - O d i l e , F r a n c e ) Hormones and cell regulation 1. Organisms. Cells. Metabolism. Regulation. Role of Hormones I. Title. II. Nunez, J . (Jacques), 1927 III Dumont, J .E . (Jacques E.), 1931 IV. Säries 574.87*61 ISBN 0-86196-229-X First published in 1989 by John Libbey Eurotext Ltd 6 rue Blanche, 92120 Montrouge, France. (1) 47 35 85 52 ISBN 0 86196 229-X John Libbey & Company Ltd 13 Smiths Yard, Summerley Street, London SW18 4HR, England. (1) 947 27 77 Institut National de la Sante et de la Recherche Medicale 101 rue de Tolbiac, 75654 Paris Cedex 13, France. (1)45 84 14 41 ISBN 2 85598 400 9 ISSN 0768-3154 © 1989 Colloques INSERM/John Libbey Eurotext Ltd, All rights reserved Unauthorized publication contravenes applicable laws IV Proceedings of the annua l European Sympos ia on Hormones and Ce l l Regulation he ld every autumn since 1976 have been published by Elsevier B iomed ica l Press i n a series co-edited by I N S E R M ( * } from Volume 1 to Volume 9. The l O t h Symposium held i n 1985 and the next ones are now publ ished as co-editions by J o h n Libbey Eurotext and I N S E R M i n the series "Colloques I N S E R M " (Vol. 139, Vol. 153, Vol . 165, Vol. 176, Vol. 198). <5|c) except Vol. 7 published by Elsevier V Contents S o m m a i r e VI I Preface IX Foreword X A v a n t - p r o p o s XI I L i s t and address of Speakers L i s t e et adresse des o r a t e u r s S U R F A C E R E C E P T O R S A N D C Y C L A S E S R E C E P T E U R S D E S U R F A C E E T C Y C L A S E S 3 M . Chinkers Guanylate cyclase as a cell surface receptor L a g u a n y l a t e cyclase c o m m e recepteur de surface c e l l u l a i r e 7 P. J JVL Van Haastert Transmembrane signal transduction i n D i c t y o s t e l i u m m u t a n s T r a n s d u c t i o n t r a n s m e m b r a n a i r e d u s i g n a l chez Dictyostel ium mutans 15 Y. Salomon C a 2 + r equ i rement of MSH- r e cep t o r funct ion : an u n u s u a l example among G-protein associated peptide hormone receptors E x i g e n c e en C a 2 * de l a f o n c t i o n r e c e p t e u r de l a M S H : u n e x e m p l e i n h a b i t u e l p a r m i les r e c e p t e u r s d ' h o r m o n e s p e p t i d i q u e s associes ä l a p r o t e i n e G 21 F. Fahrenholz, H . Luzius and D A . Jans I r revers ib le V 2 Vasopressin receptor ac t i va t i on : effect on down-regulation of the c -AMP mediated cel lular response A c t i v a t i o n i r r e v e r s i b l e d u recepteur V2 de l a Vasopressine : effet s u r le retrocontröle nögatifde l a reponse c e l l u l a i r e mediöe p a r l ' A M P c 27 J . M . Henley and E A Barnard AMPA-sensi t ive excitatory aminoacid receptors i n the chick bra in R e c e p t e u r s d ' a c i d e s a m i n e s e x c i t a t e u r s s e n s i b l e s ä l ' A M P A d a n s l e c e r v e a u de p o u l e t 33 F. Libert, M. Parmentier, A. Lefort, C. Dinsart, J . Van Sande, C. Maenhaut, M.J . Simons, J . E . Dumont and G. Vassart Homology c l on ing of c D N A s a m p l i f i e d by the Po lymerase c h a i n reaction. Identification of four new members of the G-protein coupled receptor family C l o n a g e p a r h o m o l o g i e d ' A D N c amplifies p a r l a r e a c t i o n en c h a t n e de l a P o l y m e r a s e . I d e n t i f i c a t i o n de q u a t r e n o u v e a u x m e m b r e s de l a f a m i l l e des recepteurs couples ä l a p r o t e i n e G X V R E G U L A T I O N O F G E N E E X P R E S S I O N R E G U L A T I O N D E L ' E X P R E S S I O N G E N I Q U E 39 M . Schatt, S. Wieland and S. Rusconi Promoter and enhancer act ivat ion propert ies of the glucocort icoid receptor P r o p r i e t e s d ' a c t i v a t i o n d u p r o m o t e u r et de l ' a m p l i f i c a t e u r d u r e c e p t e u r des g l u c o c o r t i c o i d e s 45 M . Boshart, F. Weih, A . Schmidt, D. Nitsch, F. Stewart and G. Schütz Transc r ip t i ona l regu la t ion of the tyrosine aminotransferase gene : structure of a regulatory switch R e g u l a t i o n t r a n s c r i p t i o n n e l l e d u g e n e de l a t y r o s i n e a m i n o t r a n s f e r a s e : s t r u c t u r e d ' u n c o m m u t a t e u r r e g u l a t e u r 49 E.R. Simpson, S. Graham-Lorence, C . J . Corbin, J . C . Merr i l l , M.S. Mahendroo and C R . Mendelson Regulat ion of expression of the gene encoding aromatase cytochrome P-450 R e g u l a t i o n de Vexpression d u g e n e c o d a n t p o u r V a r o m a t a s e c y t o c h r o m e P - 4 5 0 57 P. Flores, A. Gutman, J . L . Imler, A. Lloyd, J . Schneikert, C. Wa-sylyk and B. Wasylyk A P I and P E A 3 are nuclear targets for transcript ion activation by non-nuclear oncogenes A P I e t P E A 3 s o n t d e s c i b l e s n u c l e a i r e s d e l ' a c t i v a t i o n de l a t r a n s c r i p t i o n p a r des oncogenes n o n n u c l e a i r e s G R O W T H F A C T O R S F A C T E U R S D E C R O I S S A N C E 65 T .J . Velu, P. Martin, W.C. Vass, K. Heiin, A. Ritzhaupt, L. Begui-not, J.T. Schiller and D.R. Lowy The epidermal growth factor receptor and its role i n cell transformation L e r e c e p t e u r d u f a c t e u r de c r o i s s a n c e g p i d e r m i q u e et son r o l e dans l a t r a n s f o r m a t i o n c e l l u l a i r e 71 M . Mallat, B. Chamak, C. Thery and D. Leroy Microg l ia l cell functions dur ing bra in development F o n c t i o n s des c e l l u l e s m i c r o g l i a l e s p e n d a n t le d e v e l o p p e m e n t d u c e r v e a u C O N T R O L M E C H A N I S M S I N O T H E R S Y S T E M S M E C A N I S M E S D E CONTRÖLE D A N S D ' A U T R E S S Y S T E M E S 79 A. Diu, M . Fevrier, P. Mollier and J . Theze Control of B cell activation i n humans Contröle de V a c t i v a t i o n des c e l l u l e s B chez V k o m m e X V I 85 R. Bernards, J . M . O'Brien, D.M. Marcus, D.M. Albert, T. Jacks and R A Weinberg Towards an an imal models for retinoblastoma Vers un m o d e l e a n i m a l d u r e t i n o b l a s t o m e 91 H.R. Schöler, R. Ba l l ing , A .K . Hatzopoulos, N. Suzuk i and P. Gruss TVanscriptional activity of the octamer moti f i n embryonic stem cells and preimplantat ion embryos A c t i v i t e t r a n s c r i p t i o n n e l l e d u m o t i f ociamärique d a n s les c e l l u l e s souches e m b r y o n n a i r e s et les e m b r y o n s de p r e i m p l a n t a t i o n I O N C H A N N E L S C A N A U X I O N I Q U E S 99 S.J.H. Ashcroft and R M . Ashcroft The role of the ATP-sensit ive K-channel i n stimulus-response coupling i n pancreatic ß-cell L e r o l e d u c a n a l p o t a s s i u m s e n s i b l e ä l ' A T P dans le c o u p l a g e S t i m u l u s -reponse de l a c e l l u l e ß d u p a n c r e a s 105 E .E . Strehler, R. Heim, R. Fisher, P. James, T. Vorherr, G. Vogel, M A Strehler-Page and E . Carafoli The p lasma membrane Ca 2 * pump : structural , functional and genetic aspects of isoform diversity L a p o m p e C a 2 + de l a m e m b r a n e p l a s m i q u e : a s p e c t s s t r u c t u r a u x , f o n c t i o n n e l s e t g e n e t i q u e s de l a d i v e r site d'isoformes 111 R. Serrano and R. Perona Growth control by proton transport : evolutionary considerations and novel approaches based on the cloned yeast proton pump Contröle de l a c r o i s s a n c e p a r le t r a n s p o r t de p r o t o n s : c o n s i d e r a t i o n s e v o l u t i o n n i s t e s et n o u v e l l e s a p p r o c h e s basees s u r l a p o m p e ä p r o t o n s c l o n e e de l a l e v u r e 117 C. Frei in, P. Vigne and C. Van Renterghem M e m b r a n e events invo l v ed i n the act ion of endothe l in and other vasoconstricting hormones E v e n e m e n t s m e m b r a n a i r e s i m p l i q u e s d a n s V a c t i o n de V e n d o t h e l i n e et d ' a u t r e s h o r m o n e s v a s o c o n s t r i e t i v e s XVII Hormones and C e l l R e g u l a t i o n . N° 14, Eds J . Nunez, J.E. Dumont Colloque INSERM/J. Libbey Eurotext Ltd © 1989. Vol. 198, pp. 45-47 TVanscriptional regulation of the tyrosine amino-transferase gene : structure of a regulatory switch Michae l Boshart , F a l k Weih, Andrea Schmidt, Doris N i tsch , Franc is Stewart and Günther Schütz I n s t i t u t e of C e l l and T u m o r B i o l o g y , G e r m a n Cancer Research Center, I m N e u e n h e i m e r F e l d 280, D - 6 9 0 0 H e i d e l b e r g , F R G INTRODUCTION To understand the d i f fe rent ia t ion processes which y i e l d the various c e l l u l a r phenotypes, i t is necessary to elucidate mechanisms by which genes are se lec t i ve l y expressed. Of part icu lar importance for the establishment of a given pattern of gene ac t i v i t y i s the interplay between Control l ing genes and s ignal ing molecules such as hormones. Furthermore, i t seems clear that t i s sue-spec i f i c patterns of gene a c t i v i t y depend on both pos i t ive and negative regulatory factors. The tyrosine aminotransferase (TAT) gene i s an example of a gene whose expression i s control led by pos it ive and negative factors and by hormones. TAT expression i s regulated not only by glucocorticoids and by the peptide hormone glucagon acting via the cAMP pathway, but also by two genetically defined, trans-acting loc i (Fig. 1). F i r s t , a dominant negative regulator, termed t i s sue- spec i f i c extinguisher (Tse-1), has been defined by intertyp ic somatic c e l l hybrids and mapped to a small region of human chromosome 17 (K i l l a r y and Fournier, 1984; Lern et a l . 1989). Second, a posit ive regulator has been postulated to account for the lethal pheno-type of certain albino mice carrying a homozygous deletion around the albino locus on chromosome 7. TAT as well as several other 1 iver - spec i f i c enzymes are not expressed in the l i v e r of these newborn albino mice (Gl uecksohn-Waelsch, 1979). Since the structural gene for TAT is not deleted, and has been mapped to a chromosome other than 7, i t has been suggested that the deletion at the albino locus removes a regulatory locus (Schmid et a l . , 1985). Previously, we have shown that glucocorticoid responsiveness of TAT expression i s confered by a conditional enhancer 2500 bp upstream of the transcr ipt ion s tart s i t e (Jantzen .et a l . , 1987). Here we show that a 1 i ver-specif ic enhancer even further upstream of the TAT promoter, medi ates the effect of the dominant negative regulator Tse-1 as well as responsiveness to cAMP. This enhancer has structural and functional character ist ics of a signal transducer and we suggest that i t works as a regulatory switch which controls the hormone triggered timed onset of expression of the TAT gene in the newborn l i v e r . 45 EXPRESSION IN SPECIFIC CELLS: HEPATOCYTE SPECIFIC EXPRESSION TISSUE-SPECIFJC EXTINGUISHER ( 7s©-17 ) 2. CONTROL OF DEVELOPMENTAL ACTIVATION: PERINATAL ACTIVATION 3. CONTROL IN RESPONSE TO METABOLIC REQUIREMENTS: INDUCTION BY GLUCOCORTICOiDS AND cAMP c-LOCUS LINKED TRANS -ACT1VAT0R Fig. 1 Control of TAT gene expression RESULTS AND DISCUSSION To ident i fy c i s -act ing sequences mediating the comp lex t ranscr ipt ional regulation of the TAT gene, we fused the TAT promoter including d i f ferent portions of i t s 5 ' - f lanking region to the universal reporter gene chlor-amphenicol acetyl transferase (CAT) and trans ient ly transfected these constructs into various c e l l l i nes . F i r s t , we found that a sequence 3600 bp upstream of the transcr ipt ion start s i te strongly activated CAT expression in well d i f -ferentiated rat hepatoma ce l l s (FT02B) but not in rat f ib rob la s t s . A series of 5 ' - and 3 ' -delet ion mutants defined a sequence of 80 bp absolutely essential for transcr ipt ional Stimulation. This sequence confered hepatoma-specific act ivat ion to the heterologous TK promoter. The same sequence also mediated response to hormonal Signals transduced via the cAMP pathway. We also investigated whether th i s sequence was the target for dominant negative regulation by the product of the t i s sue-spec i f i c extinguisher (Tse-1) locus. To th i s end we transfected the same constructs used to define the 1 iver - spec i f i c enhancer into a hepatoma microcell hybrid l i ne (Lern et a l . , 1989) which contains a smal1 segment of human f ibroblast chromosome 17, carrying and expressing the Tse-1 locus. The enhancer was inactive in th i s ce l l l i ne . However, induction with cAMP was able to overcome extinction completely, thus revealing a functional antagonism between Tse-1 and the signal transduction pathway. As a f i r s t step towards understanding the mechanism of ext inct ion of enhancer function by Tse-1, we sought to ident i fy the spec i f i c sequences required for 1 i ve r - spec i f i c enhancer a c t i v i t y , for induction by cAMP and for ext inct ion by Tse-1. A complete set of clustered point mutants covering the enhancer was constructed and transfected into rat hepatoma c e l l s . Within the 80 bp minimal enhancer fragment two Short DNA sequences were found, each of which was absolutely essential for enhancer function. Each of the two sequences was inact ive on i t s own, i f pl aced in front of the heterologous TK promoter. However, multiple copies of these sequences confered strong t ranscr ipt ional Stimulation onto the TK promoter. A multimer of the dista l 26 bp sequence was responsive to cAMP and was subject to negative regulation by Ts e-1. Again the functional antagonism between Ts e-1 and the cAMP-pathway was observed; cAMP induction completely reversed the 46 negative regulation by Tse-1. In vivo footprint ing reveal ed character i st ic changes in DMS-reactivity at th i s sequence element which correlated with (i) cAMP induction, ( i i ) the presence of the Tse-1 carrying chromosome fragment, and ( i i i ) the re l i e f from extinction by cAMP. A multimer of the proximal 18 bp element behaved as a l i v e r ce l l spec i f i c act ivator of t ranscr ipt ion. In the natural context of the enhancer the d i s ta l cAMP- and Tse-l-responsive element must cooperate with the proximal l i v e r -spec i f i c element to overcome the requirement fo r multimerisation. A r t i f i c i a l combination of the 26 bp- and 18 bp-sequences created an element with a l l the regulatory properties of the entire TAT enhancer. Thus, the structure of the enhancer exemplifies the concept of the modul ar architecture of regulatory elements: a cAMP responsive module and a 1iver-spec i f i c module must.cooperate to make up a functional unit with regulatory properties unique to the combination of both. The s t r i c t ce l l - type spec i f i c i t y of th i s combination i s guaranteed by a double control and by the absence of redundancy: both modules are absolutely essential and both are inactive in f ib rob la s t s . In the case of the cAMP-responsive element, which might be recognized by an ubiquitous factor, Ts e-1 exerts negative control in f ib rob las t s . As the balance between Tse-1 ac t i v i t y and cAMP induction i s c r i t i c a l for a c t i v i t y of one component which i s synerg i s t ica l ly interacting with a second component, the TAT enhancer must have the properties of a sensit ive switch responding to changes in the Tse-l/cAMP balance with dramatic changes in overall a c t i v i t y . Therefore, one attract ive model woul d give Ts e-1 a central role in prenatal repression of TAT. Ac t i v i t y of Ts e-1 in the l i v e r would decrease during l i v e r development rendering the repressed TAT gene increasingly responsive to hormonal Stimulation towards the end of gestation. The timed onset of TAT expression around b i r th would then be triggered by the strong release of gluconeogenic hormones as a consequence of neonatal hypoglycemia. In fac t , TAT can be induced prematurely, days before b i r th by administration in utero of glucagon (acting v ia cAMP) (Greengard, 1970). REFERENCES Gl uecksohn-Waelsch, S. (1979): Genetic control of morphogenetic and biochemical d i f fe ren t i a t i on : lethal albino deletions in the mouse. Cell 16, 225-237. Greengard, 0. (1970): The developmental act ivat ion of enzymes in rat l i v e r . In Mechanisms of Hormone Action, Vol. I, G. Litwack, ed. (New York: Academic Press) , pp. 53-85. Jantzen, H.M., Strähle, U. , Gloss, B., Stewart, F., Schmid, W., Boshart, M., Mtksicek, R., Schütz, G. (1987): Cooperati vi ty of glucocorti coid response elements located far upstream of the tyrosine aminotransferase gene. Ce l l 49, 29-38. K i l l a r y , A.M. and Fournier, R.E.K. (1984): A genetic analysis of ext inct ion: trans-dominant loc i regulate expression of 1 iver - spec i f i c t r a i t s in hepatoma hybrid c e l l s . Cel l 38, 523-534. Lern, J . , Chin, A.C., Thayer, M.J. , Leach, R.J. and Fournier, R.E.K. (1989): Coordinate regulation of two genes encoding gluconeogenic enzymes by the trans-dominant 1ocus Tse-1. Proc. Natl. Acad. Sei . USA 85, 7302-7306. Schmid, W., Müller, G. , Schütz, G. and Gl uecksohn-Waelsch, S. (1985): Deletions near the albino locus on chromosome 7 of the mouse affect the level of tyrosine aminotransferase mRNA. Proc. Nat l . Acad. Sei. USA 82, 2866-2869. 47 

A genetic analysis of extinction: trans-dominant loci regulate expression of 1iver-specific traits in hepatoma hybrid cells.

Cooperati vi ty of glucocorti coid response elements located far upstream of the tyrosine aminotransferase gene.

Coordinate regulation of two genes encoding gluconeogenic enzymes by the trans-dominant 1ocus Tse-1.

Deletions near the albino locus on chromosome 7 of the mouse affect the level of tyrosine aminotransferase mRNA.

Genetic control of morphogenetic and biochemical differentiation: lethal albino deletions in the mouse.

The developmental activation of enzymes in rat liver.

Transcriptional regulation of the tyrosine aminotransferase gene

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Transcriptional regulation of the tyrosine aminotransferase gene

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